Diagnosis of Renal Osteodystrophy Among Chronic Kidney Disease Patients

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1 Diagnosis of Renal Osteodystrophy Among Chronic Kidney Disease Patients Samina S. Khan, MD, MPH, MBA; Mohammad R. Iraniha, MD Dr. Khan is an Assistant Professor of Medicine and Dr. Iraniha is a Research Associate at Tufts University School of Medicine, Boston, Massachusetts. OBJECTIVE: The purpose of this review was to study the prevalence of and establish an association between biochemical markers and the underlying rate of bone turnover in renal osteodystrophy. METHODS: Using the PubMed database, we undertook a systematic review of literature using studies that included bone histology in combination with serum biochemical markers among chronic kidney disease (CKD) patients, published between 1985 and Studies having at least 3 of 7 serum biochemical markers were chosen for this review. RESULTS: Of the dialysis patients who were recipients of 1,701 bone biopsies, 41% had hyperparathyroid bone disease, 5% had osteomalacia, and 33% had adynamic bone disease. Among CKD patients not on dialysis, of a total of 1,316 bone biopsies, 34% had hyperparathyroid bone disease, 19% had osteomalacia, and 8% had adynamic bone disease. Dialysis patients who had high-turnover bone disease compared with those with low bone turnover had signifi cantly higher levels of parathyroid hormone, serum alkaline phosphatase, bone-specifi c alkaline phosphatase, and osteocalcin. A similar relationship was observed among CKD patients not on dialysis. There was signifi cant individual variation in bone turnover biochemical markers. CONCLUSIONS: A combination of serum biochemical markers might predict underlying renal osteodystrophy better than would individual biochemical markers. A predictive model using bone histology and biochemical markers can be developed in the future. The overall prevalence of chronic kidney disease (CKD) in the adult population in the United States is 16.8%. 1 CKD is associated with multiple complications, and renal osteodystrophy (ROD) is significant among them. 2 Secondary hyperparathyroidism (SHPT) is an accompaniment of ROD, resulting from disturbances in the regulation of parathyroid hormone (PTH), calcium (Ca), phosphorus (P), and vitamin D. Levels of vitamin D begin to decrease as early as CKD stage 2, and simultaneously PTH levels begin to increase. 3 As CKD progresses, serum levels of phosphate increase, whereas serum levels of calcium decrease, 4 which serves as a stimulus to PTH secretion. Hyperphosphatemia seems to be an important risk factor for the development of SHPT; however, SHPT can occur during stage 3 of kidney failure, before the development of hyperphosphatemia. 4,5 Impaired calcitriol synthesis is one of the major factors contributing to the development of secondary hyperparathyroidism in patients with CKD. 4 ROD is associated with high morbidity and mortality, 6-8 as patients with end-stage kidney disease (ESKD) are at increased risk of bone loss and hip fracture. 9,10 The incidence of fracture in ESKD is reported to be 1% per year for the hip and about 2.6% for any other fracture, 11,12 although the incidence of hip fracture in the general population is only 0.07% 0.22%. 13 Duration of kidney replacement therapy, history of kidney transplant, exposure to glucocorticoids, and both very high and low levels of parathyroid hormone (PTH), in addition to general risk factors like older age, female sex, low body weight, postmenopausal status, osteoporosis history, and family history of osteoporosis or history of previous fracture, are among the significant risk factors. 14 The quality of life in patients with ROD is primarily affected by musculoskeletal problems such as bone pain, muscle weakness, growth retardation, and skeletal deformity. 15 œ TABLE I. Overall histological distribution of ROD among dialysis patients. Studies (n) Biopsies (n) ABD OM Normal MOD SHPT (33%) 91 (5%) 89 (5%) 230 (13.5%) 698 (41%) ROD, renal osteodystrophy; ABD, adynamic bone disease; OM, osteomalacia; MOD, mixed osteodystrophy; SHPT, secondary hyperparathyroid bone disease. February 2009 Dialysis & Transplantation 1

2 Renal Osteodystrophy in CKD Patients ROD among CKD patients can be the result of either increased bone turnover, decreased bone turnover, or a mixture of both. ROD is broadly classified into: osteitis fibrosa (OF), osteomalacia (OM), adynamic bone disease (ABD), and mixed osteodystrophy (MOD). 16 Although patients with a mild to moderate degree of CKD rarely experience symptoms, these skeletal changes develop years before symptoms arise. 17 As therapy for ROD varies, it is essential to establish the underlying diagnosis before assigning appropriate treatment. At present, bone biopsy is the gold standard for diagnosis of ROD; however, because of its invasive nature and overall complexity, clinicians rely on serum PTH levels for the TABLE II. Histological distribution of ROD among dialysis patients in individual studies. References Biopsies (n) ABD OM Normal MOD SHPT Chazan et al., 57 3 (5.3%) 16 (28.1%) 15 (26.3%) 23 (40.3%) DeVita et al., 20 N/A N/A Aluminum associated: 2; osteoporosis: 1 5 (1 associated osteomalacia) 11 HPT; 1 OM HPT Hercz et al., % 4.2% Mild 17.7% 6.2% 22.5% Goodman et al., PD N/A N/A 3 mild N/A 11 (78.6%) Torres et al., HD: 49; CAPD: 32 Ureña et al., HD 32% CAPD 48% N/A N/A N/A HD: 32%; CAPD: 14% (23.8%) N/A N/A N/A 32 (76.2%) Fletcher et al., 73 3 (4%) Coen et al., (22.0%) N/A N/A 9 (22.0%) 23 (56.0%) Forerol et al., (2.9%) 20 mild 2 (2.9%) 31 (44.3%) Olaizola et al., 20 8 (40%) N/A 5 mild (25%) 7 (35%) Haese et al., (35%) 10 (10%) 13 (13%) 21 (21%) 21 (21%) Gerakis et al., (3.2%) 6 (9.7%) 40 (64.5%) Sanchez et al., N/A 16 mild N/A 5 (8.8%) Jarava et al., (28%) 2 N/A 5 Mild: 8; OF: Pecovnik Balon & 30 5 (16%) N/A N/A 15 OF 10 Bren, Changsirikulchai et (41.1%) 2 (3.6%) 3 (5.4%) 11 (19.6%) 16 (28.6%) al., Ballanti et al., 37 5 (13.5%) 7 (18.9%) 4 mild (10.8%) 5 (13.5%) 16 (43.3%) Marie et al., LBT: 28 N/A N/A N/A HTO or normal: 23 Coen et al., (20.5%) 2 (5.1%) N/A 17 (43.6%) 12 (30.8%) Continued 2 Dialysis & Transplantation February 2009

3 TABLE II. (Continued) References Biopsies (n) ABD OM Normal MOD SHPT Chu et al., (28.6%) 1 (7.1%) N/A 3 (21.4%) 6 (42.9%) Ng et al., % 10% 12% mild 8% 21% Gal-Moscovici & Popovtzer, % 13% 21% 40% Coen et al., LTO: 14; adynamic: 7 N/A 1 normal Coen et al., 38 3 (7.9%) 3 (7.9%) N/A 11 (28.9%) 21 (55.3%) Van Eps et al., N/A LTO 4 3 (17.7%) N/A HTO: 10 Barreto et al., (58%) 1 (1%) 3 (3%) 24 (25%) 12 (12%) HD, hemodialysis; PD, peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; LTO, low turnover; HTO, high turnover; N/A, not applicable or not available. diagnosis and treatment of ROD among CKD patients. The purpose of our systematic review was to study the prevalence of and evaluate an association between serum biochemical markers such as Ca, P, PTH, alkaline phosphatase (ALP), bone specific alkaline phosphatase (bsalp), osteocalcin (OC) or vitamin D, and bone histology in order to predict a diagnosis of ROD. Methods Using the PubMed database, we undertook a systematic review of the literature for studies describing the distribution of ROD among CKD patients on dialysis and CKD patients not on dialysis [search 1: kidney failure, chronic (MeSH) AND renal osteodystrophy (MeSH); search 2: renal osteodystrohy (MeSH) and biochemical markers; search 3: kidney failure, chronic (MeSH) AND biochemical markers AND bone histomorphometry; search 4: dialysis (MeSH) AND biochemical markers AND bone histology]. Of all the retrieved results, we selected articles published between 1985 and 2007 that provided information on bone histology in combination with serum biochemical markers of patients with CKD. Of the 42 articles we reviewed, 3 were in Spanish, 1 was in Japanese, and the rest were in English. Of these 42 articles, we selected 13 studies that had at least 3 of these 7 serum biochemical markers: PTH, Ca, P, ALP, bsalp, OC, and vitamin D. Because serum biochemical markers were expressed either as mean standard deviation (SD) or standard error (SE), we converted SE to SD by using the formula SE SD/ n. A weighted average of the mean and SD were calculated. To calculate the mean, we multiplied the number of patients in each category by the means of the serum biochemical markers and divided by the total number of patients in the study. To calculate the weighted standard deviation, the second power of each standard deviation was added, and then the square root of the sum was taken. We divided patients into those with high-turnover (HTO) bone disease and those with low-turnover (LTO) bone disease, according to bone histology. All patients with mixed bone disease, mild, moderate, or severe hyperparathyroidism, and OF cystica were included in the highturnover group, whereas patients with ABD and OM were included in the low-turnover group. If there were several categories in each histological type such as mild, moderate, and severe hyperparathyroidism, we calculated the weighted average for serum biochemical markers in each category. Results We reviewed 42 articles, of which 26 included dialysis patients and 16 included CKD patients not on dialysis. Table I summarizes the overall histological distribution of ROD among dialysis patients. Of the patients receiving 1,701 bone biopsies, 41% had hyperparathyroidism, 5% OM, and 33% ABD. The rest were classified as normal bone or mixed bone disease. There was variability among studies in reporting bone histology. Some studies did not report the histological types of all biopsies, and 1 study reported 17 patients with OM among 33 with SHPT. Table II summarizes the histological distribution of ROD among dialysis patients in individual studies. The presence of ABD significantly varied in each study, ranging from 4% to 63%. Table III summarizes the histological distribution of ROD among CKD patients not on dialysis. Of these patients who received 1,316 bone biopsies, 34% had hyperparathyroidism, 19% OM, and 8% ABD. Table IV summarizes the histological distribution of ROD among CKD patients not on dialysis TABLE III. Histological distribution of ROD among CKD patients not on dialysis. Studies (n) Biopsies (n) (8%) ABD OM Normal MOD SHPT 255 (19%) 269 (20%) 244 (18%) 453 (34%) œ February 2009 Dialysis & Transplantation 3

4 Renal Osteodystrophy in CKD Patients TABLE IV. Histological distribution of ROD among CKD patients not on dialysis in individual studies. References Biopsies (n) ABD OM Normal MOD SHPT Mora et al., N/A OM with OF: 112 Lindenau et al., CKD: mild 53, moderate 40, advanced 44 N/A CKD: mild 12, moderate 3, advanced 4 Neither OM or OF: 40 CKD: mild 5, moderate 9, advanced 5 N/A OF alone: 175 CKD: mild 24, moderate 21, advanced 29 CKD: mild 12, moderate 7, advanced 6 Sellares et al., N/A 7 (13.2%) 1 (1.9%) 7 (13.2%) Severe: 12; mild: 26 Hutchison et al., 30 8 (27%) 2 (7%) 1 (3%) 4 (13%) OF: Sato, N/A 4 (6.5%) N/A N/A OF: 1; mild: 57 Hamdy et al., (5.1%) With HPT: 24; 44 (25%) N/A 98 (55.7%) OM alone: 1 Coen et al., (11.8%) 7 (9.2%) 10 (13.2%) MOD: mild 26, advanced 22 2 HP (2.6%) Lafage et al., (25%) 2 (12.5%) 7 (43.7%) N/A 3 OF Ballanti et al., (22.2%) 3 (11.1%) N/A MOD: advanced 9, mild 7 2 (7.4%) Coen et al., (11.4%) 8 (10.1%) 10 (12.6%) 50 (63.3%) 2 (2.5%) Duothat et al., (9.6%) 10 (19.2%) N/A 10 (19.2%) Severe: 13; mild: 14 Spazovski et al., 84 23% 12% 38% 18% 9% mild Bervoets et al., (22.6%) 10 (11.9%) 32 (38.1%) 15 (17.9%) 8 (9.5%) Lobao et al., (low densitometry) 52.5% 42.5% N/A 5% N/A Lehmann et al., Stages 3/4: 35 Stages 3/4: 3 (8.6%) Stages 3/4: 2 (5.7%) Stages 3/4: 7 normal, 4 mild Stages 3/4: 3 (8.6%) Stages 3/4: OF 16 (45.7%) in the individual studies. The presence of ABD significantly varied in each study, ranging from 5.1% to 27%. Table V presents serum biochemical markers in dialysis patients with ROD (LTO versus HTO). There were a total of 221 patients in the low-turnover and 303 in the high-turnover group. When compared with the LTO group, patients with HTO bone disease had significantly higher levels of ALP, bsalp, OC, and ipth. There was no significant difference between 2 groups in terms of Ca and P. Table VI presents biochemical markers in CKD patients not on dialysis with ROD (LTO versus HTO). There were a total of 78 patients in the LTO group and 29 patients in the HTO group. When compared with the LTO bone disease group, patients with HTO bone disease had significantly higher bsalp, 4 Dialysis & Transplantation February 2009 OC, and ipth. The level of Ca, P, and ALP were not significantly different between the 2 groups. Figure 1 shows the comparison of histological variations in ROD between dialysis patients and CKD patients not on dialysis. ABD is more common in dialysis patients than in CKD patients not on dialysis. Figures 2 and 3 show a comparison of all serum biochemical markers in dialysis and CKD patients not on dialysis with LTO and HTO bone disease, respectively. Discussion ROD comprises a wide spectrum of manifestations that includes a high-turnover state such as hyperparathyroid bone disease and a low-turnover state such as OM and ABD. 18 ROD occurs early in the course of CKD and worsens as kidney function declines. Bone disease is common among patients with CKD stage 5, and by the time dialysis is initiated, almost all patients are affected. 19 Our goal was to evaluate the prevalence of ROD and establish an association between serum biochemical markers associated with the rate of bone turnover such as PTH, ALP, bsalp, or OC, with underlying bone histology, in order to establish an accurate diagnosis of ROD, which is essential to assign treatment. We found an overall high prevalence of adynamic bone disease 33% and 8% among CKD patients on dialysis and CKD patients not on dialysis, respectively. However, individual studies have found a prevalence of adynamic disease as high as 58% and 52% among dialysis patients and CKD

5 TABLE V. Biochemical markers in dialysis patients with ROD (low turnover versus high turnover). References Patients (n) Ca (mg/dl) P (mg/dl) AP (IU/L) bsalp OC ( g/l) Low turnover Hercz et al., N/A N/A N/A 77 Urena et al., N/A N/A Fletcher et al., N/A N/A Coen et al., N/A N/A N/A Gerakis et al., (54 140) N/A N/A N/A 15 (4 37) Jarava et al., N/A Monier et al., N/A N/A Coen et al., N/A Total (n) 221 Mean SD High turnover Hercz et al., N/A N/A N/A Ureña et al., N/A N/A Fletcher et al., N/A N/A Coen et al., N/A N/A N/A Gerakis et al., (95 430) N/A N/A N/A 714 ( ) Jarava et al., N/A N/A Monier et al., N/A N/A 530 Coen et al., N/A Total (n) 303 Mean SD Vit D ipth patients not on dialysis, respectively. We found hyperparathyroid bone disease was the most common type of ROD in both CKD patients on dialysis and those not on dialysis. In the dialysis group, PTH, ALP, bsalp, and OC were significantly higher in those with HTO bone disease than in those with LTO bone disease. Similarly, in CKD patients not on dialysis, PTH, bsalp, and OC were significantly higher in those with HTO bone disease than in those with LTO bone disease. Various methods such as serum biochemical markers, imaging studies, and histopathological studies are currently used to diagnose ROD. Ca, P, PTH, ALP, and bsalp are among the most commonly used serum biochemical markers. Similar to previous studies, we found no significant association between serum Ca or P with rate of bone turnover in ROD. 20,21 PTH is most commonly used as a serum biochemical marker to determine the underlying bone disease in CKD patients. Biologically active PTH circulates mostly as a 1 84 amino-acid peptide. 22 PTH fragments containing carboxy-terminal parts of the molecule of varying length are also present in circulation. First-generation immunoradiometric assays of so-called intact PTH not only measured full-length PTH (1 84) but also recognized large PTH fragments lacking the amino terminus The Nichols assay for the estimation of intact parathyroid hormone (i-pth) overestimates parathyroid gland function by recognizing both the whole PTH-1-84 molecule (identified as a cyclase-activating PTH-CAP) and N-truncated fragments of PTH-7-84 (identified as a cyclase-inactive PTH-CIP). 24 Currently, a third-generation assay, which measures 1-84 PTH, and whole PTH and provides 7-84 PTH, 25 manufactured by Scantibodies (San Clemente, Calif.), and the ratio of 1-84/7-84 has shown to be associated with rate of bone turnover. 26 Serum levels of PTH can predict the presence and severity of SHPT without correlating with the underlying bone disease. 24,27 Levels of ipth in dialysis patients œ February 2009 Dialysis & Transplantation 5

6 Renal Osteodystrophy in CKD Patients TABLE VI. Biochemical markers in CKD patients not on dialysis with ROD (low turnover versus high turnover). References Patients (n) Ca (mg/ dl) P (mg/dl) ALP (IU/L) bsalp OC ( g/l) Vit D ipth Low turnover Hutchison et al., N/A N/A Coen et al., N/A N/A N/A Coen et al., N/A Coen et al., 17 N/A N/A N/A N/A Spasovski et N/A al., Total (n) 78 Mean SD High turnover Hutchison et al., N/A N/A Coen et al., ( ) 7.3 ( ) (78 225) N/A N/A N/A 897 ( ) Coen et al., N/A Coen et al., 2 N/A N/A (78 225) N/A N/A 23 (18 28) ( ) Spasovski et ( ) 6.3 ( ) 91 (50 223) 42 (20 126) 76 (11 183) N/A 201 ( ) al., Total (n) 29 Mean SD bsalp, bone-specifi c alkaline phosphatase; OC, osteocalcin. more than 4 times normal and less than 2 times normal are associated with a greater frequency of HTO and LTO bone disease, respectively. 28 Although PTH is a good indicator of bone metabolism, the sensitivity and specificity to diagnose HTO bone disease with levels <500 ng/ml and ABD disease with levels <100 ng/ml are inadequate. 28 Bone biopsy studies among dialysis patients revealed that bone remodeling and response to PTH varies among various racial groups. 29,30 In a study of 76 ESKD patients, the majority of African American patients with LTO bone disease had higher serum PTH levels than those of whites with LTO bone disease. 29 In our systematic review, although individual patients had variations in the correlation of PTH with underlying bone turnover, at an aggregate level there was a good correlation between the level of PTH and bone turnover among both dialysis and non-dialysis patients. ALP is a marker of osteoblast-mediated bone formation that does provide useful information in conjunction with PTH measurement. 31 The combination of low serum bsalp ( 7 ng/ml) and low serum PTH is very suggestive of LTO bone disease. 32 Similarly, an elevated bsalp (>200 ng/ml) alone or in combination with increased serum PTH (>200 ng/ml) has been shown to be highly sensitive and specific for HTO bone disease. 33 Although bsalp may provide some advantage, some experts believe that total serum ALP plus PTH levels are adequate to evaluate bone formation. 18 In our review, we found good correlation between serum ALP and bone turnover among dialysis patients; however, such correlation was not present among CKD patients not on dialysis. Bone-specific ALP, a more specific 6 Dialysis & Transplantation February 2009

7 FIGURE 1. Comparison of ROD distribution among dialysis patients and CKD patients not on dialysis. FIGURE 2. Comparison of serum biochemical markers in dialysis patients with low- and high-turnover bone disease. FIGURE 3. Comparison of serum biochemical markers in CKD patients not on dialysis with lowand high-turnover bone disease. indicator of osteoblastic activity, was not reported in all articles used in our review. However, based on our data, there was a good correlation between bsalp and bone turnover. In dialysis patients with HTO bone disease, the levels of bsalp were almost 4 times higher than those in LTO bone disease. Similarly, in CKD patients not on dialysis with HTO bone disease, the levels of bsalp were almost double than those in LTO bone disease. The serum level of OC an indicator of bone formation reflects the rate of OC synthesis by osteoblasts. Among biomarkers, which reflect bone formation, the OC assay is preferred because of its high discriminant power and is better characterized in terms of clinical application. 34 In our review, OC was reported in a limited number of articles; however, using the aggregate data, there was a good correlation between level of OC and bone turnover. Among dialysis patients with HTO bone disease, OC levels were almost 3 times greater than those in LTO bone disease. Similarly, in CKD patients not on dialysis with HTO bone disease, the levels of OC were almost twice those of patients with LTO bone disease. Additionally, as an indicator of osteoblastic activity, other biomarkers such as tartrate-resistant acid phosphatase, serum C-terminal telopeptide of collagen type I, and pyridinolin crosslinks as indicators of the resorption process can be specifically measured to estimate bone turnover and are important for noninvasive diagnosis of ROD. 35,36 Radiographic examination of bone can provide important information regarding the presence of hyperparathyroidism such as osteopenia, subperiosteal resorption, and cysts. However, radiological finding are less sensitive and do not determine renal osteodystrophy. Among patients with advance bone disease, plain films may reveal subperiosteal resorption in severe OF or looser zones in severe OM. 18 The importance of bone mineral density (BMD) measurement is unclear in patients with ROD; however, a lower BMD has shown to predict fracture risk in dialysis patients. 37,38 In CKD patients, distal radius is the preferred site for BMD measurement, as BMD of the spine may be misleading because of aortic calcifications. The prevalence of osteopenia and/or osteoporosis also increases with a decreasing glomerular filtration rate. 39 In a study of patients with CKD, the highest levels of BMD in the lumbar spine, hip, and distal forearm were found in those with a glomerular filtration rate between 70 and 110 ml/min/1.73 m 2 (stages 1 and 2 CKD), whereas those with a glomerular filtration rate between 6 and 26 ml/min/1.73 m 2 (stage 4 CKD) had the lowest BMD levels. The abnormalities in bone metabolism that might be responsible for the decreased BMD were not characterized in these studies. The presence of osteoporosis œ February 2009 Dialysis & Transplantation 7

8 Renal Osteodystrophy in CKD Patients is a strong predictor of increased risk for fractures in the general population. Although the importance of BMD and risk reduction in fractures by treatment of osteoporosis has not been established among CKD patients, serial measurement of BMD using dual energy x-ray absorptiometry can identify patients with a continuous decline in BMD and increased risk of fractures. A combination of serum biochemical markers can predict the underlying rate of bone turnover with more accuracy. A study of 30 chronic hemodialysis patients in whom a bone biopsy was performed in conjunction with assessment of biochemical markers showed that if only PTH was taken into consideration, 36.6% of patients were correctly classified according to their diagnosis. However, if both PTH and bone densitometry were taken into consideration, 46.6% were classified correctly. Considering PTH and radiological changes in clavicular and metacarpal bones such as periosteal, endosteal, and intracortical resorption, 60% of patients were classified correctly. 40 In conclusion, we found that on a collective basis serum levels of PTH, AP, bsalp, and osteocalcin are high in highturnover bone disease and low in low-turnover bone disease. Use of a combination of 3 or more markers may determine underlying renal osteodystrophy with more accuracy than individual biochemical markers. However, a bone biopsy should be encouraged in younger patients with ESKD, with PTH levels between 200 and 500 pg/dl, where other biochemical markers are not well defined. Limitations Similar to any systematic review, lack of individual patient data, variability in histological classification within studies, and lack of use or reporting of all biochemical markers were limitations of our review. Conclusions The most common histological type of ROD among dialysis and CKD patients not on dialysis was hyperparathyroid bone disease; however, the presence of adynamic bone disease was significant in both groups. 8 Dialysis & Transplantation February 2009 A combination of 2 or 3 serum biochemical markers such as PTH, ALP, bsalp, and OC might help clinicians to more accurately diagnose ROD in order to assign treatment with vitamin D. D&T References 1. Prevalence of chronic kidney disease and associated risk factors United States, MMWR Morb Mortal Wkly Rep. 2007;56: Thomas R, Kanso A, Sedor JR. Chronic kidney disease and its complications. Prim Care. 2008;35: Andress DL. Vitamin D treatment in chronic kidney disease. Semin Dial. 2005;18: Sanchez CP, Goodman WG, Salusky IB. Prevention of renal osteodystrophy in predialysis patients. Am J Med Sci. 1999;317: González EA, Sachdeva A, Oliver DA, Martin KJ. Vitamin D insuffi ciency and defi ciency in chronic kidney disease. A single center observational study. Am J Nephrol. 2004;24: Coburn JW, Norris KC, Nebeker HG. Osteomalacia and bone disease arising from aluminum. Semin Nephrol. 1986;6: Gabriel R. Morbidity and mortality of long-term haemodialysis: a review. J R Soc Med. 1984;77: Piraino BM, Rault R, Dominguez JH, Puschett JB. Renal osteodystrophy in patients on hemodialysis for more than 10 years. Miner Electrolyte Metab. 1986;12: Mittalhenkle A, Gillen DL, Stehman-Breen CO. Increased risk of mortality associated with hip fracture in the dialysis population. Am J Kidney Dis. 2004;44: Nickolas TL, Leonard MB, Shane E. Chronic kidney disease and bone fracture: a growing concern. Kidney Int. 2008;74: Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58: Ball AM, Gilllen DL, Sherrard DJ, et al. Risk of hip fracture among dialysis and renal transplant recipients. JAMA. 2002;288: Kanis JA, Johnell O, De Laet C, et al. International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res. 2002;17: 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: Tejwani NC, Schachter AK, Immerman I, Achan P. Renal osteodystrophy. J Am Acad Orthop Surg. 2006;14: Ritz E, Merke DJ, Lukas PA. Genesis of bone disease in uremia. In: Peck WA, ed. Bone in Mineral Research. 5th ed. Amsterdam, The Netherlands: Elsevier; 1987: Hamdy NA, Kanis JA, Beneton MN, et al. Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure. BMJ. 1995;310: Moe S, Drüeke T, Cunningham, J, et al. Defi nition, evaluation, and classifi cation of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69: Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis. 2000;36: DeVita MV, Rasenas LL, Bansal M, et al. Assessment of renal osteodystrophy in hemodialysis patients. Medicine (Baltimore). 1992;71: Fletcher S, Jones RG, Rayner HC, et al. Assessment of renal osteodystrophy in dialysis patients: use of bone alkaline phosphatase, bone mineral density and parathyroid ultrasound in comparison with bone histology. Nephron. 1997;75: Jüppner H, Potts Jr JT. Immunoassays for the detection of parathyroid hormone. J Bone Miner Res. 2002;17(Suppl 2):N81-N Friedman PA. PTH revisited. Kidney Int Suppl. 2004;91:S13-S Martin KJ, Olgaard K, Coburn JW, et al. Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy. Am J Kidney Dis. 2004;43: Souberbielle JC, Friedlander G, Cormier C. Practical considerations in PTH testing. Clin Chim Acta. 2006;366: Negri AL, Alvarez Quiroga M, Bravo M, et al. [Whole PTH and 1-84/84 PTH ratio for the non invasive determination of low bone turnover in renal osteodysthrophy]. Nefrologia. 2003;23: Gal-Moscovici A, Popovtzer MM. New worldwide trends in presentation of renal osteodystrophy and its relationship to parathyroid hormone levels. Clin Nephrol. 2005;63: K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Available at: Sawaya BP, Butros R, Naqvi S, et al. Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease. Kidney Int. 2003;64: Sawaya BP, Monier-Faugere MC, Ratanapanichkich P, et al. Racial differences in parathyroid hormone levels in patients with secondary hyperparathyroidism. Clin Nephrol. 2002;57: Sprague SM. The role of the bone biopsy in the diagnosis of renal osteodystrophy. Semin Dial. 2000;13: Urena P, De Vernejoul MC. Circulating biochemical markers of bone remodeling in uremic patients. Kidney Int. 1999;55: Ureña P, Hruby M, Ferreira A, et al. Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients. J Am Soc Nephrol. 1996;7: Taylor AK, Leuken SA, Libanati C, Baylink DJ. Biochemical markers of bone turnover for the clinical assessment of bone metabolism. Rheum Dis Clin North Am. 1994;20: Mazzaferro S, Pasquali M, Ballanti P, et al. Diagnostic value of serum peptides of collagen synthesis and degradation in dialysis renal osteodystrophy. Nephrol Dial Transplant. 1995;10: Ureña P, Ferreira A, Kung VT, et al. Serum pyridinoline as a specifi c marker of collagen breakdown and bone metabolism in hemodialysis patients. J Bone Miner Res. 1995;10: Yamaguchi T, Kanno E, Tsubota J, et al. Retrospective study on the usefulness of radius and lumbar bone density in the separation of hemodialysis patients with fractures from those without fractures. Bone. 1996;19:

9 38. Ureã P, Bernard-Poenaru O, Ostertag A, et al. Bone mineral density, biochemical markers and skeletal fractures in haemodialysis patients. Nephrol Dial Transplant. 2003;18: Rix M, Andreassen H, Eskilden P, Langdahl B, Olgaard K, et al. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int. 1999;56: Pecovnik Balon B, Bren A. Bone histomorphometry is still the golden standard for diagnosing renal osteodystrophy. Clin Nephrol. 2000;54: Chazan JA, Libbey NP, London MR, et al. The clinical spectrum of renal osteodystrophy in 57 chronic hemodialysis patients: a correlation between biochemical parameters and bone pathology fi ndings. Clin Nephrol. 1991;35: Hercz G, Pei Y, Greenwood C, et al. Aplastic osteodystrophy without aluminum: the role of suppressed parathyroid function. Kidney Int. 1993;44: Goodman WG, Ramirez JA, Belin TR, et al. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int. 1994;46: Torres A, Lorenzo V, Hernández D, et al. Bone disease in predialysis, hemodialysis, and CAPD patients: evidence of a better bone response to PTH. Kidney Int. 1995;47: Coen G, Ballanti P, Bonucci E, et al. Bone markers in the diagnosis of low turnover osteodystrophy in haemodialysis patients. Nephrol Dial Transplant. 1998;13: Velasquez Forero F, Altamirano E, Ramos PT. High frequency of iron bone deposits in a Mexican population with renal osteodystrophy. Nephrol Dial Transplant. 1998;13(Suppl 3): Olaizola I, Aznarez A, Jorgetti V, et al. Are there any differences in the parathyroid response in the different types of renal osteodystrophy? Nephrol Dial Transplant. 1998;13(Suppl 3): D Haese PC, Couttenye MM, Lamberts LV, et al. Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of end-stage renal failure patients. Clin Chem. 1999;45: Gerakis A, Hadjidakis D, Kokkinakis E, et al. Correlation of bone mineral density with the histological fi ndings of renal osteodystrophy in patients on hemodialysis. J Nephrol. 2000;13: Carmen Sánchez M, et al. Parathormone secretion in peritoneal dialysis patients with adynamic bone disease. Am J Kidney Dis. 2000;36: Jarava C, Armas JR, Palma A. [Study of renal osteodystrophy by bone biopsy. Age as an independent factor. Diagnostic value of bone remodeling markers]. Nefrologia. 2000;20: Changsirikulchai S, Domrongkitchaiporn S, Sirikulchayanonta V, et al. Renal osteodystrophy in Ramathibodi Hospital: histomorphometry and clinical correlation. J Med Assoc Thai. 2000;83: Ballanti P, Coen G, Mazzaferro S, et al. Histomorphometric assessment of bone turnover in uraemic patients: comparison between activation frequency and bone formation rate. Histopathology. 2001;38: Monier-Faugere MC, Geng Z, Mawad H, et al. Improved assessment of bone turnover by the PTH-(1-84)/large C-PTH fragments ratio in ESRD patients. Kidney Int. 2001;60: Coen G, Ballanti P, Balducci A, et al. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant. 2002;17: Chu P, Chao TY, Lin YF, et al. Correlation between histomorphometric parameters of bone resorption and serum type 5b tartrate-resistant acid phosphatase in uremic patients on maintenance hemodialysis. Am J Kidney Dis. 2003;41: Ng AH, Hercz G, Kandel R, Grynpas MD. Association between fl uoride, magnesium, aluminum and bone quality in renal osteodystrophy. Bone. 2004;34: Coen G, Mantella D, Manni M, et al. 25-Hydroxyvitamin D levels and bone histomorphometry in hemodialysis renal osteodystrophy. Kidney Int. 2005;68: Coen G, Ballanti P, Balducci A, et al. Renal osteodystrophy: alpha-heremans Schmid glycoprotein/fetuin-a, matrix GLA protein serum levels, and bone histomorphometry. Am J Kidney Dis. 2006;48: Van Eps CL, Jeffries JK, Anderson JA, et al. Mineral metabolism, bone histomorphometry and vascular calcifi cation in alternate night nocturnal haemodialysis. Nephrology (Carlton). 2007;12: Barreto FC, Barreto DV, Moysés RM, et al. K/DOQIrecommended intact PTH levels do not prevent lowturnover bone disease in hemodialysis patients. Kidney Int. 2008;73: Mora Palma FJ, Ellis HA, Cook DB, et al. Osteomalacia in patients with chronic renal failure before dialysis or transplantation. Q J Med. 1983;52: Lindenau K, Kokot F, Vetter K, et al. Current status of diagnosis and treatment of renal osteodystrophy in the predialysis period. Contrib Nephrol. 1988; Lorenzo Sellares V, Torres Ramírez A, Hernández Marrero D, et al. [A study using nondecalcifi ed bone biopsy of the incidence and presentation forms of renal osteodystrophy]. Med Clin (Barc). 1991;96: Hutchison AJ, Whitehouse RW, Boulton HF, et al. Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease. Kidney Int. 1993;44: Sato T. [Studies on the pathogenesis and pathophysiology of renal osteodystrophy. II. Bone histology of chronic renal failure patients at the time of starting hemodialysis]. Nippon Jinzo Gakkai Shi. 1994;36: Coen G, Mazzaferro S, Ballanti P, et al. Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study. Nephrol Dial Transplant. 1996;11: Lafage-Proust MH, Combe C, Barthe N, Aparicio M. Bone mass and dynamic parathyroid function according to bone histology in nondialyzed uremic patients after long-term protein and phosphorus restriction. J Clin Endocrinol Metab. 1999;84: Coen G, Ballanti P, Bonucci E, et al. Renal osteodystrophy in predialysis and hemodialysis patients: comparison of histologic patterns and diagnostic predictivity of intact PTH. Nephron. 2002;91: Douthat WG, Garay G, de Arteaga J, et al. [Biochemical and histological spectrum of renal osteodystrophy in Argentina]. Nefrologia. 2003;23(Suppl 2): Spasovski GB, Bervoets AR, Behets GJ, et al. Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis. Nephrol Dial Transplant. 2003;18: Bervoets AR, Spasovski GB, Behets GJ, et al. Useful biochemical markers for diagnosing renal osteodystrophy in predialysis end-stage renal failure patients. Am J Kidney Dis. 2003;41: Lobão R, Carvalho AB, Cuppari L, et al. High prevalence of low bone mineral density in pre-dialysis chronic kidney disease patients: bone histomorphometric analysis. Clin Nephrol. 2004;62: Lehmann G, Stein G, Hüller M, et al. Specifi c measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry. Kidney Int. 2005;68: February 2009 Dialysis & Transplantation 9