Optimizing bone health in chronic kidney disease

Maturitas 65 (2010) 325–333

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Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Optimizing bone health in chronic kidney disease Solenne Pelletier a,b , Roland Chapurlat b,∗ a b

Départment of Nephrology, Hospital Edouard Herriot, Lyon, France INSERM Research Unit 831, Université de Lyon, 5 Place d’Arsonval, Lyon, France

a r t i c l e

i n f o

Article history: Received 17 December 2009 Accepted 20 December 2009

Keywords: Chronic kidney disease Osteoporosis Fracture Bone Renal failure

a b s t r a c t Phosphocalcic metabolism disorders often complicate chronic kidney disease (CKD) and worsen as kidney function declines, with a consequence on bone structural integrity. The risk of fracture exceeds that of the normal population in both patients with pre-dialysis CKD and end-stage renal disease (ESRD). The increasing incidence of CKD, the high mortality rate induced by hip fracture, the decreased quality of life and economic burden of fragility fracture make the renal bone disorders a major problem of public health around the world. Optimizing bone health in CKD patients should be a priority. Bone biopsy is invasive. Dual-energy X-ray absorptiometry, commonly used to screen individuals at risk of fragility fracture in the general population, is not adequate to assess advanced CKD because it does not discriminate fracture status in this population. New non-invasive three-dimensional high-resolution imaging techniques, distinguishing trabecular and cortical bone, appear to be promising in the assessment of bone strength and might improve bone fracture prediction in this population. Therapeutic intervention in the chronic kidney disease-mineral and bone disorders (CKD-MBD) should begin early in the course of CKD to maintain serum concentration of biological parameters involved in mineral metabolism in the normal recommended ranges, prevent the development of parathyroid hyperplasia, prevent extra-skeletal calcifications and preserve skeletal health. In this paper, we review studies of mineral and bone disorders in patients with CKD and ESRD, the utility of current techniques to assess bone health and the preventive and therapeutic strategies for managing CKD-MBD. © 2010 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of bone disorders in patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impaired bone strength in patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessment of bone health in patients with CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Transiliac bone biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Bone radiographs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. DXA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Conventional central and peripheral quantitative computed tomography (QCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. High resolution magnetic resonance imaging (HR-MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. High resolution peripheral quantitative computed tomography (HR-pQCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Biochemical markers of bone turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: aBMD, areal bone mineral density; b-ALP, bone-specific alkaline phosphatase; CKD, chronic kidney disease; CKD-MBD, chronic kidney disease-mineral and bone disorders; CT, computed tomography; DXA, dual energy X-ray absorptiometry; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HR-MRI, high-resolution magnetic resonance imaging; HR-pQCT, high-resolution peripheral quantitative computed tomography; iPTH, intact parathyroid hormone; KDIGO, kidney disease improving global outcomes; MRI, magnetic resonance imaging; PTH, parathyroid hormone; pQCT, peripheral quantitative computed tomography; QCT, quantitative computed tomography; ROD, renal osteodystrophy; SHPT, secondary hyperparathyroidism; vBMD, volumetric bone mineral density; WHO, World Health Organization. ∗ Corresponding author. Tel.: +33 472117481. E-mail address: [email protected] (R. Chapurlat). 0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.12.021

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7. 8.

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6.1. Control of serum phosphate, calcium and PTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Use of vitamin D and its metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Use of calcimimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Parathyroidectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Control of metabolic acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7. Physical exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8. Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives in CKD-MBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Phosphocalcic metabolism disorders often complicate chronic kidney disease (CKD), appearing very early in the evolution of CKD, when the estimated glomerular filtration rate (eGFR) declines below 60 ml/min/1.73 m2 , and worsen as kidney function decline. The impairment in the normal physiological mechanisms regulating blood levels of calcium, phosphate, vitamin D and parathyroid hormone (PTH) has an impact on bone structural integrity. The term of chronic kidney disease-mineral and bone disorders (CKD-MBD) has been chosen by the Kidney Disease Improving Global Outcomes (KDIGO) to refer more adequately to the complications of mineral abnormalities [1]. Thus, CKD-MBD is used for the broader syndrome of mineral metabolism, skeletal disorders and vascular or soft tissue calcifications that occur during CKD. The control of CKD-MBD, particularly involving vascular calcifications, is important to decrease morbidity and mortality in the CKD population. The old term ‘renal osteodystrophy’ (ROD) is now used to refer to the bone pathology. Skeletal changes may occur years before the main clinical manifestations of bone disorders in CKD (pain and fractures) [2]. The risk of fracture exceeds that of the normal population in both patients with pre-dialysis CKD and end-stage renal disease (ESRD). Thus, a 2-fold increase in hip fracture risk in patients with moderateto-severe kidney disease and a 4-fold increase in hemodialysis patients, compared with population-based controls in the United States have been observed [3,4]. Young dialysis patients (age <45 years) have a relative risk of hip fracture that is 80-fold higher than that of age and sex-matched controls subjects [4]. Studies have identified risk factors for fracture in dialysis patients which included traditional risk factors for hip fracture in the general population plus peripheral vascular disease and either low or high PTH levels [5,6]. The increasing incidence of CKD, the high mortality rate induced by hip fracture, the decreased quality of life and economic burden of fragility fracture make the renal bone disorders a major problem of public health around the world. This review will focus on the problem of bone health in patients with CKD and ESRD, the usefulness of current techniques to assess bone status and to identify patients at risk for fragility fracture and preventive and therapeutic strategies for managing CKD-MBD. 2. Methods This article is based on a review of publications in peer-reviewed journals collected by the authors, using Pubmed. The keywords: used for the search were: acidosis; bisphophonates; bone biopsy; bone imaging; bone microarchitecture; bone mineral density; CKD; CKD-MBD; calcimimetic; DXA; ESRD; FGF-23; fracture; KDIGO; K/DOQI; mineral-bone disorder; osteoporosis; ROD; renal bone

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disease; vascular calcification; calcium; phosphate; parathyroid hormone; vitamin D. This is not a systematic review. We have selected the articles that were felt to be relevant to describe the optimization of bone health among patients with CKD. 3. Pathophysiology of bone disorders in patients with CKD Several metabolic and hormonal abnormalities appear after a relatively mild reduction in glomerular filtration rate, including hyperphosphatemia, hypocalcemia, increased secretion of PTH, decreased kidney synthesis of calcitriol (1,25(OH)2 D3 ), chronic metabolic acidosis, premature hypogonadism and alterations in growth factors. An increase in PTH levels and a decrease in serum calcitriol are the earliest mineral metabolism disturbances in CKD, while serum phosphorus and calcium are generally altered later in the course of CKD [7]. Indeed, in a large cross-sectional study of outpatients with early CKD, low serum 1,25(OH)2 D3 was found in 13% of patients with eGFR > 80 ml/min, in more than 60% of those with eGFR < 30 ml/min and this decline is nearly linear with the decrease of eGFR [8]. Elevated PTH (>65 ng/l) occurred in 12% of patients with an eGFR > 80 ml/min, and increased markedly when eGFR decreased. However, serum calcium and phosphate were normal down to eGFR below 40 ml/min. Thus, phosphocalcic metabolism abnormalities are found in virtually all patients with ESRD. Fig. 1 summarizes factors involved in the pathogenesis of CKD-MBD. All these abnormalities are closely interrelated and their contribution to impaired bone strength is complex. Additionally, some patients with CKD are treated with glucocorticoids, which have bone side effects. 4. Impaired bone strength in patients with CKD Morphologic bone impairment can appear long before ESRD, as shown by a review of the prevalence of the types of ROD as determined by bone biopsy in patients with CKD-MBD. Analyzed studies were carried out between 1983 and 2006. Eighty-four percent of CKD patients (eGFR < 60 ml/min/1.73 m2 ) had histologic evidence of bone disease (32% osteitis fibrosa, 20% mixed bone disease, 8% osteomalacia, 6% mild disease and 18% adynamic bone disease) [9]. The prevalence of the different types of ROD changes when patients receive dialysis. Only 2% of dialysis patients have normal histomorphometric analyses of bone biopsy. In hemodialysis patients and patients receiving peritoneal dialysis, the review showed the following: osteitis fibrosa (34% vs 18%), mixed lesions (32% vs 5%), adynamic bone (19% vs 50%), ostemomalacia (10% vs 5%), and mild disease (3% vs 20%), respectively [9]. Bone status in CKD patients can be compromised by three types of damage potentially associated in a same patient: bone remodelling impairment (osteitis fibrosa, adynamic bone disease,

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Fig. 1. Factors involved in the pathogenesis of CKD-MBD.

and mixed renal osteodystrophy), defect in mineralization of bone matrix (osteomalacia) and bone loss. Osteoporosis is defined by a “systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture” [10]. In clinical practice, the diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) of the spine and proximal femur. DXA measures the bone mineral content, which divided by the measured area, provides a value for the areal bone mineral density (aBMD). The World Health Organization (WHO) threshold definition of osteoporosis is a T-score at or below −2.5 [11] but bone quality also characterizes bone strength [12]. Bone quality is determined by architecture and microarchitecture, bone remodelling, bone mineralization, collagen properties and microdamage accumulation (e.g., microfractures) [12,13]. Many CKD patients have low bone mass and it seems that the prevalence of osteoporosis in CKD population exceeds the prevalence in the general population [14]. Typically, osteoporosis in CKD patients may appear when bone turnover is high, as in secondary hyperparathyroidism with osteitis fibrosa, and in all other cases where bone resorption exceeds bone formation rates (e.g., gonadal hormone deficiency). In the early stages of CKD, when fragility fracture occurs, the diagnosis of osteoporosis can be made in the absence of biochemical mineral abnormalities that might suggest some form of CKD-MBD [15]. Nevertheless, in ESRD patients for which CKD-MBD is extremely common, there is no universally accepted criteria defining osteoporosis. Thus, with worsening CKD, the diagnosis of osteoporosis can be best suggested to explain a fragility fracture when other forms of ROD have been excluded [15].

tical thickness and the appearance of cortical porosity may affect bone strength. Trabecular bone is a combination of rods and plates. Single trabeculae are 50–200 ␮m thick, and bone marrow fills the 200–1000 ␮m wide interspaces between trabeculae [16]. Trabecular bone strength depends on bone quantity but also on trabecular microarchitecture parameters, such as the trabecular number, separation and connectivity [17]. 5.1. Transiliac bone biopsy Histomorphometric analysis of transiliac bone biopsy, performed after double tetracycline labelling, is the only method to ascertain the histological diagnosis of ROD. It is a two-dimensional analysis which remains the gold standard for assessing bone turnover, bone mineralization and bone loss. In clinical practice, bone biopsy is not widely used because it is invasive. Cortical and trabecular microarchitecture can be distinguished with two-dimensional histomorphometry. In the research area, a new imaging technique (Micro-CT, resolution 20 ␮m) performed on intact bone biopsy samples, provides three-dimensional representation of trabecular microarchitecture and can provide estimates of mechanical strength (finite element analysis) [18]. 5.2. Bone radiographs They are not indicated for the assessment of bone disease of CKD, but they are useful in detecting peripheral vascular calcification and bone disease due to ␤2-microglobulin amyloidosis. They are also useful to detect vertebral fracture, which in two-thirds of patients, are not diagnosed when they occur.

5. Assessment of bone health in patients with CKD

5.3. DXA

Two components of bone can be distinguished: cortical bone and trabecular bone. More than 80% of the skeleton is made of cortical bone, which has a compact structure. A decrease in cor-

This technique is commonly used to screen individuals at risk of fragility fracture in the general population, but its value among patients with advanced CKD and ESRD is debated [19–21]. Indeed,

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aBMD appears to be decreased in this population but aBMD does not discriminate between those with and without prevalent fractures [20,21]. Moreover, aBMD does not predict the type of ROD; aBMD can be low, normal or high in each of the major forms of ROD [22,23]. In addition, aortic calcifications, which are common in ESRD patients, may lead to overestimation of spine aBMD. Thus, the KDIGO does not recommend the routine use of DXA in advanced CKD with evidence of CKD-MBD [9]. Finally, DXA analyses three-dimensional objects in only 2dimensions and its resolution does not allow to distinguish cortical and trabecular bone compartments whereas in patients with CKD bone impairment may differ across the two compartments. For example, chronic excess PTH secretion is catabolic for cortical bone, causing thinning of the cortex and increased cortical porosity [24,25]. Therefore, other imaging techniques have been developed in order to improve spatial resolution, to provide more accurate three-dimensional assessment of bone microarchitecture and finally more estimates bone quality and strength.

5.4. Conventional central and peripheral quantitative computed tomography (QCT) Applied to central sites (lumbar spine and proximal femur) and to peripheral sites (distal radius and tibia), QCT provides a trabecular and cortical volumetric measurement of BMD (vBMD), and not an areal projection like DXA. In patients without CKD, indices measured by micro-CT of bone biopsy samples correlate well with comparable trabecular and cortical parameters measured by QCT [26]. Peripheral QCT has been used to assess bone microarchitecture in pre-dialysis patients, dialysis patients and in kidney transplant recipients [27–31]. Two of these studies at the distal radius were reported in pre-dialysis patients and five in dialysis patients [32]. Among them, Obatake et al. described a decrease in total, cortical and trabecular vBMD in 53 pre-dialysis patients after one-year follow-up [30]. In a cross-sectional study, Russo et al. demonstrated a reduction in cortical vBMD in 39 hemodialysis patients in comparison to 67 controls, whereas there was no difference for trabecular vBMD [28]. Negri et al. reported a selective loss of cortical bone and thickness at the radius in 22 patients in peritoneal dialysis in comparison to 27 controls. There was no correlation between pQCT cortical parameters and areal BMD measured at the lumbar spine and femoral neck by DXA [33]. These studies suggest cortical and trabecular vBMD impairment in pre-dialysis and selective cortical vBMD impairment in ESRD patients. Nevertheless, pQCT cannot provide information about trabecular microarchitecture owing to its resolution (350 ␮m), which is inadequate to distinguish a trabecular element (≈100 ␮m).

5.5. High resolution magnetic resonance imaging (HR-MRI) HR-MRI is a non-ionizing imaging technique providing threedimensional representation of cortical and trabecular bone microarchitecture at peripheral sites (distal radius, tibia and calcaneus). Wehrli et al. used this imaging technique to assess bone microarchitecture in 17 subjects with ESRD under the age of 50 years [34]. Although there was substantial variability among the patients, cortical thickness was significantly lower than controls matched for age, gender and body mass index. Larger and longitudinal studies with HR-MRI might allow assessing fracture risk non-invasively in patients with CKD and ESRD, but this technique may be more promising to evaluate the trabecular bone, because it is difficult to detect cortical edges with MRI and the accuracy of cortical thickness measurement is poor.

Fig. 2. Distal tibia analysis with HR-pQCT in a 54 years man who has been treated with hemodialysis for 1 year. He suffered from hypertensive nephrosclerosis and needed a haemostatic nephrectomy. His cortical structure is very heterogeneous and he had qualitative alteration of trabecular bone. A that time, the ionized calcium was 1.24 mmol/l, iPTH 556 ng/l and 25(OH)vitamin D was 36 ng/ml. The KT/V was 1.36.

5.6. High resolution peripheral quantitative computed tomography (HR-pQCT) HR-pQCT is a newer technique which nominal isotropic voxel size is 82 ␮m, providing in vivo a three-dimensional representation of cortical and trabecular bone microarchitecture in approximately 9 mm in the axial direction of distal radius and tibia [35]. Compared with MRI, HR-pQCT has the advantage of directly visualizing the bone and has a faster acquisition. The effective dose is less than 3 ␮Sv per measurement (less than half a day’s natural background radiation), and the measurement time is 3 min [35,36]. Bacchetta et al. have examined bone microarchitecture with HR-pQCT at the radius and tibia in 70 CKD patients older than 50 years (46 men and 24 women) and compared outcomes with those of controls belonging to two cohorts of healthy subjects (men and women) comparable for age and gender. The mean age of CKD patients was 70.8 ± 8.5 years, mean eGFR was 34 ± 12 ml/min/1.73 m2 and mean serum intact PTH (iPTH) was 87 ± 59 pg/ml. In this study, both CKD men and women experienced a moderate but significant trabecular impairment, positioning CKD patients values between those of normal and osteopenic controls. Cortical thickness in men was also significantly decreased compared to healthy controls [37]. Bone microarchitecture has been examined with HR-pQCT at the right tibia in 19 hemodialysis men (mean dialysis vintage 2.2 ± 1.9 years) and compared outcomes with those of 52 stage II–IV CKD men (mean eGFR 33 ± 12 ml/min/1.73 m2 ) [37]. Fig. 2 shows a three-dimensional reconstruction of tibia using HR-pQCT in a hemodialysis man. Hemodialysis men had a greater cortical and trabecular bone impairment compared to CKD men, despite being younger (47 ± 16 years vs 66 ± 16 years respectively). Thus, this new technique may improve bone microarchitecture assessment in CKD and ESRD patients. Longitudinal studies are necessary to confirm that this non-invasive technique allows improving bone fracture prediction in this population. 5.7. Biochemical markers of bone turnover During bone turnover, some proteins are released into the blood circulation and their measurement in serum or urine is used to assess osteoblastic and osteoclastic activities. They are summarized in Table 1. Serum markers are preferred because they are more reproducible. Some of these markers are excreted by the kidney with an accumulation in the serum when glomerular filtration decreases. Bone-specific alkaline phosphatase (b-ALP) and

S. Pelletier, R. Chapurlat / Maturitas 65 (2010) 325–333 Table 1 Biochemical markers of bone turnover. Bone formation Bone-derived turnover markers of collagen Serum Procollagen type I carboxyterminal propeptide (PICP) Procollagen type I aminoterminal propeptide (PINP)

Bone resorption Serum Type I collagen carboxyterminal cross-linking telopeptide (CTX)

hormone but measures a new PTH species called amino-PTH which biological activity is unknown, thus bringing new complexity to the PTH measurement field [47,48]. Because the superiority of the third-generation PTH assay is not established to improve the predictive value for the diagnosis of underlying bone disease or other serum markers of bone turnover [49,50], the KDIGO suggests to continue to use the widely available second-generation PTH assays in routine clinical practice [9]. 6. Prevention and treatment

Urine Deoxypyridinoline Pyridinoline Type I collagen carboxyterminal cross-linking telopeptide (CTX) Type I collagen aminoterminal cross-linking telopeptide (NTX) Others bone markers Serum Bone-specific alkaline phosphatase Osteocalcin

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Serum Tartrate-resistant acid phosphatase 5b

tartrate-resistant acid phosphatase 5b are interesting in the course of CKD because their serum concentration are unaffected by renal dysfunction [38]. There is a good correlation between b-ALP and iPTH and histomorphometric parameters of bone formation in a study of hemodialysis patients [39]. Positive predictive value of iPTH with b-ALP is 96.8% for high turnover bone disease and 80% for low turnover bone disease [39]. In a review of bone markers in uremic patients, serum b-ALP is suggested to be the most sensitive and specific marker to evaluate the degree of bone remodeling in this population [40]. Nevertheless in an recent study, the predictive value for high versus low/normal bone turnover status was comparable for b-ALP and others bone turnover markers in ESRD patients [41]. Some studies have shown a correlation between other markers of bone turnover and histomorphometric parameters, but so far none of them have shown a superiority in predicting histological outcomes compared with serum iPTH or b-ALP in later stages of CKD-MBD. When eGFR is under 30 ml/min/1.73 m2 , the KDIGO suggest to measure serum PTH and b-ALP to evaluate bone disease, whereas measurement of bone-derived turnover markers of collagen synthesis and breakdown are currently not recommended in clinical practice [9]. Of note, there are different generations of PTH assays. PTH is a single-chain 84-amino-acid peptide hormone. This protein is present in the blood in his full-length but also in various degradation fragments. These fragments have not a clearly elucidated function and they accumulate in CKD patients [42]. Several immunoassays are available. The second generation assays use an anti-carboxyterminal antibody and either an anti-aminoterminal antibody (for example directed toward the proximal 15–20 portion of the protein, e.g., the Allegro assay) or a more distal epitope (for example directed toward the 26–32 portion of the protein like the Elecsys assay) [43]. These assays were thought to measure only the full-length 1–84 PTH and were called “intact” PTH assays, but in fact, they also react with a non-(1–84) molecular form of PTH (7–84 PTH fragment) [44]. Studies about this 7–84 fragment suggest effects that are opposite to those of the 1–84 PTH in bone and in calcium and phosphate regulation [45]. The third-generation PTH radioimmunoassay, called “whole” or “bioactive” PTH assay, uses an anti-carboxyterminal antibody and a very proximal anti-aminoterminal antibody (directed toward the 1–4 portion of the protein) [46]. This assay measuring the full-length 1–84 PTH does not measure the 7–84 fragment of the

Therapeutic intervention in the CKD-MBD should begin early in the course of CKD, when disturbances in the mineral metabolism begin. The objectives for the management of CKD-MBD in CKD patients are to maintain serum concentration of biological parameters involved in mineral metabolism in the normal recommended ranges, prevent the development of parathyroid hyperplasia, prevent extra-skeletal calcifications and preserve skeletal health. 6.1. Control of serum phosphate, calcium and PTH Hyperphosphatemia, resulting from the failure to excrete phosphorus when kidney function declines, is associated with secondary hyperparathyroidism (SHPT), ROD and vascular calcifications. The 2003 K/DOQI guidelines recommended maintaining phosphorus levels between 0.87 and 1.49 mmol/l in pre-dialysis patients and between 1.13 and 1.78 mmol/l in dialysis patients [51]. The 2009 KDIGO guidelines suggests maintaining serum phosphorus in the normal range when eGFR < 60 ml/min/1.73 m2 [9]. When the serum phosphate levels are above these targets and when the plasma level of iPTH is elevated, restricting dietary phosphate is the first line of treatment and should typically be restricted to 800–1000 mg/day [51]. Indeed, dietary phosphorus adapted to the degree of a reduction in GFR can prevent the development of hyperparathyroidism and parathyroid hyperplasia [52–54]. However, this restriction should also be adjusted for dietary protein needs to avoid malnutrition, which is common in ESRD patients [55]. Current recommendations for dietary protein intake in clinically stable chronic hemodialysis patients should be at least 1.1 g protein/kg ideal body weight/d [56]. Because phosphate is present in most foods containing protein, the addition of phosphate binders taken with meals is often required. Among them, calcium based (calcium carbonate and calcium acetate) or non-calcium-based phosphate binders (sevelamer-HCl and lanthanum carbonate) are currently used and some others are still in development. Aluminum-containing phosphate binders should be avoided because of the risk of aluminum-related bone disease and encephalopathy [57]. Approximately 99% of body calcium is contained in the skeleton. To avoid drawing calcium in the bone reservoir, the serum level of total calcium corrected for albumin level in pre-dialysis patients should be maintained within the normal range and preferably toward the lower range (2.10–2.37 mmol/l) in ESRD patients, following the K/DOQI guidelines [51]. The KDIGO suggested maintaining serum calcium in the normal range whatever the CKD stage and proposed ideally the measurement of ionized calcium to evaluate serum calcium, but this assay is more expensive, is technically more demanding, and may not be available everywhere [9]. Others suggest total calcium should be used in clinical practice because of fluctuations in albumin level in CKD patients. Maintenance of normal calcium balance and serum calcium levels in CKD depends on control of serum phosphate, vitamin D and PTH, which should be maintained within the appropriate ranges. Moreover, dialysate calcium can be adjusted and calcium salt can be administered between meals in case of hypocalcemia [51]. The KDIGO recommend restricting the dose of calcium-based

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phosphate binders in the presence of persistent or recurrent hypercalcemia or hyperphosphatemia because administration of calcium salt may contribute to the progression of vascular calcifications induced by hyperphosphoremia in hemodialysis patients [58,59], especially in case of adynamic bone [9,60]. This bone disorder is characterized by low bone formation with no osteoid accumulation and PTH levels in the low to normal range [61]. In CKD patients, iPTH measurement is used to assess SHPT (i.e., >70 pg/ml when eGFR < 60 ml/min/1.73 m2 , >110 pg/ml when eGFR < 30 ml/min/1.73 m2 and >300 pg/ml in ERSD patients) [51]. Both low and high PTH levels are identified as risk factors for fracture in dialysis patients [5,6]. The control of serum PTH is discussed thereafter. 6.2. Use of vitamin D and its metabolites Serum levels of 25-hydroxyvitamin D represent the body stores of vitamin D, which deficiency is common in CKD [62]. Moreover, serum calcitriol concentration decreases in the course of CKD because kidneys are the principal site for its production. Current recommendations are to correct 25-hydroxyvitamin D deficiency to raise serum 25-hydroxyvitamin D concentration above 30 ng/ml (75 nmol/l). This 25-OH vitamin D concentration is the threshold below which PTH starts to rise in individuals with normal renal function [63]. Whether this relationship and this threshold are similar in CKD patients and in normal individuals remains uncertain. Whether native or active, vitamin D supplementation in CKD favors the intestinal calcium absorption and reduces the serum PTH concentration among CKD patients [64]. They have not been demonstrated to reduce fracture incidence in patients with CKD, but Rix et al. showed that a treatment with alfacalcidiol maintained BMD measured by DXA among patients with moderate CKD [65]. The use of this treatment may induce development of adynamic bone when serum PTH concentration is too low. In addition, it has been suggested that calcitriol supplementation reduces mortality in CKD patients [66] and all-cause mortality risk in CKD patients is greater when serum 25-hydroxyvitamin D concentration is less than 15 ng/ml [67]. Thus, vitamin D is associated with beneficial pleiotropic actions (role in immune regulation, on heart function, in cancer prevention, in coagulation homeostasis, etc.) [68]. 6.3. Use of calcimimetics Calcimimetic agents are allosteric modulators of the parathyroid calcium-sensing receptor and have been introduced for the control of SHPT in uremic patients undergoing hemodialysis. This class of therapeutic agents suppresses PTH synthesis and secretion while simultaneously lowering serum calcium and phosphate [69]. In a pan-European observational study in dialysis patients with SHPT of varying severity, therapy with cinacalcet increased the proportion of subjects achieving the K/DOQI targets (4%, 39%, 40% and 46% for iPTH, phosphorus, calcium and calcium phosphorus product at baseline, respectively, vs 28%, 48%, 51% and 68%, respectively, at month 12) [70]. This efficacy was also reported in other studies [71]. Moreover, long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe SHPT [72]. Cinacalcet led to significant reductions in the risk of parathyroidectomy, of skeletal fracture (54% reduction of the risk) and hospitalisation resulting from cardiovascular disease, in maintenance hemodialysis patients who had uncontrolled SHPT (iPTH ≥ 300 pg/ml) [73]. A recent study suggests that calcimimetics may suppress calcification of arterial smooth muscle cells in a model of 5/6 nephrectomized rats [74]. A randomized placebo controlled trial is ongoing to demonstrate a survival benefit induced by cinacalcet.

The bone histologic response of cinacalcet was described in 19 dialysis patients with SHPT in a prospective, double-blind, placebocontrolled trial (13 controls). Bone biopsies were performed before and after one year of treatment. Cinacalcet treatment decreased evidence of osteitis fibrosa as a result of its PTH-lowering effect (diminution of activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface) while bone mineralization parameters remained normal [75]. Taken together, these data suggest that, in addition to its effects on PTH, cinacalcet had favorable effects on important clinical outcomes. 6.4. Parathyroidectomy Despite medical treatment, SHPT develops in some dialysis patients with bone fragility as a consequence. Parathyroidectomy should be recommended in patients with symptomatic and persistent serum levels of PTH > 800 pg/ml, associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical therapy [1]. Usually, subtotal parathyroidectomy or total parathyroidectomy with parathyroid tissue autotransplantation is used. After surgery, careful follow-up is required to prevent hypocalcemia. Results from the French National Observatory of Mineral Metabolism suggest that the need for surgical parathyroidectomy in hemodialysis patients has been stable since 2005 and concerns about 7% of hemodialysis patients per year in France [76]. Younger patients on long-term hemodialysis may be at a greater risk [77]. 6.5. Control of metabolic acidosis Acidosis is observed in many pre-dialysis and ESRD patients. Chronic metabolic acidosis alters the ionic composition of bone and increases bone resorption, leading to bone fragility [78,79]. Moreover, it has adverse consequences on protein and muscle metabolism (muscle wasting) [80,81]. Metabolic acidosis may be corrected by oral bicarbonate supplementation or in dialysis patients by increasing the bicarbonate concentration in dialysate fluid. A meta-analysis about “correction of chronic metabolic acidosis for chronic kidney disease patients” suggests there may be some beneficial effects on both protein and bone metabolism, but the analyzed trials were underpowered to provide robust evidence [82]. Interestingly, a role of metabolic acidosis in the inhibition of soft tissue calcification in uremic rats has been recently suggested [83]. 6.6. Bisphosphonates They are potent inhibitors of bone resorption and produce their effect by inducing osteoclasts apoptosis. They are the most commonly agents used to treat postmenopausal or glucocorticoidinduced osteoporosis and provide fracture protection in individuals with low BMD. Bisphosphonates are quickly cleared from plasma, about 50% being deposited in bone and the remainder excreted in urine. Their half-life in bone is very prolonged [84]. In early CKD patients with osteoporosis and fragility fracture and without biological abnormalities suggesting some form of CKD-MBD, the use of these drugs is safe and results in fracture reduction [85]. Bisphosphonates have been shown to be safe and efficacious in patients with eGFR as low as 30 or 35 ml/mn (depending on the drug). Importantly, compliance with calcium and vitamin D supplementation should be ensured. Serum 25-OH vitamin D should exceed 30 ng/ml before initiating an antiresorptive agent. When GFR is under 30 ml/min, bisphosphonates should not be used, to avoid adynamic bone. Nevertheless, a randomized placebo-controlled trial among 31 hemodialysis patients showed a BMD preservingeffect at the hip with low dose of alendronate at 6 months compared

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to baseline, whereas hip BMD decreased in those treated with placebo [86]. In this study, alendronate appeared to be well tolerated. The long-term bone benefit of this kind of treatment remains to be proven. The type of ROD should be determined before starting any therapy. Thus, adynamic bone disease should be excluded before initiating bisphosphonates. Indeed, reduction in bone turnover in a pre-existing inactive bone may aggravate the bone condition. Moreover, in case of SHPT with low BMD but high bone resorption, the reduction in bone resorption contributes to improved mineral apposition but induces a reduction in levels of serum ionized calcium and bisphosphonates may indirectly contribute to stimulate PTH secretion [87]. In patients with eGFR under 30 ml/min/1.73 m2 and who suffer from fragility fractures, the use of bisphosphonates is controversial and the risk/benefit ratio should be weighted carefully because of the high mortality associated to severe fragility factures. Thus, randomized prospective studies are required in order to examine the benefits of bisphosphonates in osteoporosis of ESRD patients and to make recommendations on dose and duration of treatment. Newer agents such as denosumab which blocks osteoclast differentiation, activation and survival, appear to be promising in postmenopausal osteoporosis [88]. However, the role of these agents in CKD patients remains to be evaluated. 6.7. Physical exercise With asthenia induced by uremia, many CKD patients reduce their physical activity. The National Health and Nutrition Examination Survey III Inactivity (NHANES III) examined inactivity in CKD patients (eGFR < 60 ml/min/1.73 m2 ) and showed that inactivity was present in 13.5% of the non-CKD and 28.0% of the CKD groups [89]. Immobilisation is a very important cause of bone loss and should be avoided as possible in CKD patients because of the high risk of osteopathy. In the general population and in CKD patients, the amount of weight-bearing exercise that is optimal for skeletal health in patients with osteoporosis is not known, but exercise forms an integral component of management. New measurements of physical activity are available. Among them, the SenseWear Armband (BodyMedia, Pittsburgh, PA) appears very easy to use in chronic kidney disease and is interesting because it also estimates the total daily energy expenditure which is essential to allow the provision of nutritional requirements [90]. 6.8. Nutrition

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In CKD patients, serum FGF-23 levels are positively correlated with serum phosphate and negatively with serum calcitriol and PTH [97,98]. Since FGF-23 has a counter-regulatory effect on vitamin D, the increased FGF-23 during CKD potentially reduces vitamin D activity, and thus facilitates the development of secondary hyperparathyroidism [94]. Moreover, baseline intact FGF-23 serum level (cut-off 7500 ng/l) was described as a potential predictor of refractory hyperparathyroidism at two years in 103 non-diabetic dialysis patients with mild hyperparathyroidism at baseline [99]. Urena et al. found no relationship between FGF23 and BMD in 99 hemodialysis patients, and serum markers of bone remodeling were significantly correlated with parathyroid hormone but not with FGF23 levels [100]. There is a lack of data assessing the potential role of FGF23 in renal bone disease whereas it would be interesting to study whether the FGF23 increase observed in CKD is associated with underlying bone disease. In addition, Jean et al. showed in a cohort of 219 hemodialysis patients an increased risk of mortality and vascular calcifications in patients with higher quartiles of FGF23 serum levels two years after inclusion [101]. Gutierrez et al. obtained similar results [102]. Mirza et al. have shown that an elevated serum FGF23 levels, even within the normal range, are associated with increased left ventricular mass index, with an increased risk for the presence of left ventricular hypertrophy and are independently associated with impaired vasoreactivity and increased arterial stiffness in elderly subjects [103,104]. Therapeutic reduction of FGF23 might delay the onset of secondary hyperparathyroidism, the onset of CKD-MBD, and maybe the global morbi-mortality in CKD patients [105].

8. Conclusion Bone damage appears early in the course of CKD and is common in dialysis patients. The consequence is an increased risk of fracture in the CKD population. Fractures are associated with a decreased quality of life and an excess mortality. Thus, optimizing bone health in CKD patients should be a priority. New non-invasive imaging techniques (HR-MRI and HR-pQCT) appear to be promising in the assessment of bone strength and might allow improving bone fracture prediction in this population. Longitudinal studies are requested to confirm this hypothesis. Moreover, prospective clinical trials of bone-protective agents in CKD and ESRD patients are needed to determine if early care of bone status may improve global outcome. These new imaging techniques would be useful to this aim.

Nutritional recommendations are available in CKD [55,56]. CKD patients suffer from muscle wasting, malnutrition, and inflammation that may affect bone health. Sufficient protein intakes are necessary to fight against ‘protein-energy wasting’ and to maintain the function of the musculoskeletal system. In the general population, sufficient protein intakes also decrease the complications that occur after an osteoporotic fracture [79,91].

Competing interests

7. Perspectives in CKD-MBD

Contributors

Involvement of molecules such as klotho and FGF-23 has been suggested in CKD-MBD. FGF-23 is synthesized and released in bone by osteocytes, which are differentiated osteoblastic cells. FGF-23 receptors are ubiquitously expressed but the downstream effects of FGF-23 have been localized to the kidney, parathyroid and pituitary glands [92]. From early stages of CKD, FGF-23 increases as GFR decreases, before serum phosphate has become abnormal, presumably to maintain phosphate balance [93,94]. In ESRD, FGF-23 levels may be markedly elevated [95,96].

Solenne Pelletier has performed the literature search and drafted the manuscript. Roland Chapurlat has supervised the search, drafted and edited the manuscript.

Solenne Pelletier has received a research grant from the Société Franc¸aise de Néphrologie. Roland Chapurlat receives a salary from the University of Lyon. We have no conflict of interest regarding this specific article.

Provenance and peer review Commissioned and externally peer reviewed.

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