Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density

Hans-Gernot Asmus1, Johan Braun2, Rolfdieter Krause3, Reinhard Brunkhorst4, Herwig Holzer5, Walter Schulz6, Hans-Hellmut Neumayer7, Paolo Raggi8 and Jürgen Bommer9

1 KfH Nierenzentrum Sonnenallee Berlin, Berlin, 2 KfH Nierenzentrum Nürnberg, Nürnberg, 3 KfH Nierenzentrum Moabit Berlin, Berlin, 4 KfH Nierenzentrum Hannover, Klinikum Hannover Oststadt, Podbielskistrasse 380, D-30659 Hannover, 6 Klinikum Bamberg, Bamberg, 7 Universitätsklinikum Charité, Berlin, 9 Universitätsklinikum Heidelberg, Sektion Nephrologie, Bergheimerstrasse 56a, D-69115 Heidelberg, Germany, 5 Universitätskinikum Graz, Graz, Austria and 8 Tulane University School of Medicine, New Orleans, LA, USA

Correspondence and offprint requests to: Professor Jürgen Bommer, Klinikum der Universität Heidelberg, Sektion Nephrologie, Bergheimerstrasse 56a, D-69115 Heidelberg, Germany. Email: juergen_bommer{at}t-online.de



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Calcium-based phosphate binders may induce tissue calcification, and little is known about their effects on bone density. We compared the effects of a calcium with a non-calcium phosphate binder on both arterial calcification and bone density measured by computed tomography.

Methods. Seventy-two adult haemodialysis patients were randomized to treatment with calcium carbonate (CC) or sevelamer (SEV) for 2 years. Electron beam CT scans were performed at baseline and at 6, 12 and 24 months. Serum phosphorus, calcium, calcium xphosphorus product and intact parathyroid hormone (iPTH) were measured and other routine laboratory tests were also carried out.

Results. The average calcium x phosphorus product was similar in the two treatment groups. However, patients receiving CC had significantly lower average iPTH (P<0.01), were more likely to have hypercalcaemic episodes (P = 0.03) and had significantly greater increases in coronary artery (CC median 484, P<0.0001, SEV median 37, P = 0.3118, between-group P = 0.0178) and aortic (CC median 610, P = 0.0003, SEV median 0, P = 0.5966, between-group P = 0.0039) calcification scores. The CC group also had a significant decrease in trabecular bone density (CC median –6%, P = 0.0049, SEV median +3%, P = 0.0296, between-group P = 0.0025). However, there was no significant difference in cortical bone density between the two groups.

Conclusions. This 2 year study shows that calcium carbonate use is continuously associated with progressive arterial calcification in haemodialysis patients. In addition, it suggests that it is also associated with decreased trabecular bone density. However, this latter finding requires confirmation by a study specifically devoted to this issue.

Keywords: bone; calcium; hyperphosphataemia; hyperparathyroidism; phosphate; sevelamer



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
End-stage renal disease (ESRD) is associated with hyperphosphataemia and hyperparathyroidism that often result in soft tissue calcification, osteodystrophy and bone disease. Hyperphosphataemia is strongly related to arterial calcification which is highly prevalent and has been linked to adverse cardiovascular outcomes in ESRD [1]. As a consequence, experts have recently recommended lower serum phosphorus treatment targets in this population [2]. However, the frequently used calcium-based phosphate binders do not prevent and may even favour the progression of soft tissue calcification, while they have not been shown to help reduce bone mineral loss in ESRD [3,4]. We have shown that a non-calcium-containing binder, sevelamer, was superior to calcium carbonate in preventing the progression of arterial calcification during 1 year of observation [5]. In the context of that study, we were able to follow a subgroup of the patients randomized to sevelamer or calcium carbonate in our previous report for an additional year (total of 2 years) to determine if differences in calcification progression were sustained over time. Furthermore, we utilized the archived electron beam computed tomography (EBCT) images to investigate whether progressive vascular calcification was accompanied by changes in tissue density in the lower thoracic spine.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
The study subjects were adult chronic haemodialysis patients over the age of 19 years without prior serious gastrointestinal disease, ethanol or drug dependence or abuse, active malignancy, human immunodeficiency virus (HIV) infection, vasculitis, or poorly controlled diabetes mellitus or hypertension. The subjects were recruited from dialysis centres in Nürnberg, Heidelberg, Bamberg, Hannover and Berlin in Germany, and Graz in Austria.

Protocol
After screening, patients underwent a 2 week washout period from all currently used phosphate binders (weeks –2 to 0). Patients who developed hyperphosphataemia (serum phosphorus >1.8 mmol/l) during the washout period were eligible for randomization into the treatment phase. Patients were stratified by investigative site and diabetes and randomized in a 1:1 ratio to open label sevelamer (Renagel® 800 mg tablets, GelTex Pharmaceuticals, Inc., Waltham, MA) or calcium carbonate (Sertuerner® 500 mg tablets, Sertuerner Arzneimittel GmbH, Guetersloh, Germany). The starting dose of sevelamer and calcium carbonate was determined by replacing the phosphate binder used by patients prior to the washout on a gram for gram basis. Patients were treated for 2 years. During the first year, the dose of phosphate binder was titrated to achieve a serum phosphorus level in the target range of 1.0–1.6 mmol/l and a serum calcium level <2.6 mmol/l. Physicians could prescribe aluminium as a rescue binder if the calcium x phosphorus product exceeded 5.8 mmol2/l2. Serum phosphorus, calcium and intact parathyroid hormone (iPTH) were measured at least monthly for the first 12 months then every 3 months for an additional 12 months. Testing was done at a central laboratory (Quest Diagnostics, Heston, Middlesex, UK). Laboratory measurements were made using local laboratories during the second year. In a subset of patients, we also collected data on 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, pH and pCO2.

Of the 114 randomized patients, 108 underwent an EBCT imaging procedure at day 0. Patients still under treatment underwent repeat scans at 6 and 12 months. During the first year, 13 patients in the calcium carbonate group and 19 patients in the sevelamer group were withdrawn for various reasons including adverse events (six in the calcium group and 14 in the sevelamer group), withdrawn consent (three in the calcium group), death (one in the calcium group and two in the sevelamer group) or other reasons (three in the calcium group and three in the sevelamer group) [5]. Patients completing the first 12 months of treatment (n = 82) were asked to complete a second 12 months of treatment and undergo a final EBT scan. These 82 patients had similar demographics and calcification scores to the patients who did not complete the first 12 months. During the second year, optimal study conditions with strict control by pill counts and frequent interviews were suspended so that the patients were treated under standard conditions of daily practice. Seventy-two patients agreed to participate in the study extension and 52 had repeat EBCT scans. Written informed consent was obtained from all patients. This study was conducted in compliance with the recommendations of the Declaration of Helsinki and the Ethics Committees at each of the participating medical centres.

Imaging procedure
All EBCT imaging procedures were performed on a C-150 scanner (GE-Imatron, South San Francisco, CA). A standard imaging protocol was used in this study and is described elsewhere [3]. A single expert investigator blinded to treatment assignment interpreted the EBCT scans. EBCT scans were analysed for the presence of coronary artery, thoracic aorta, aortic valve and mitral valve calcification using the Agatston score that has an interscan variability of 8–10% [3]. To determine the bone tissue density of the thoracic vertebrae, we chose the lowest intact thoracic vertebra that was completely visible in both baseline and 24 month scans. All osteophyte formations and deformities were carefully avoided, and compressed and deformed vertebrae were excluded from analysis. Furthermore, care was taken to choose the same site for analysis on the same vertebra at baseline and 24 months.

To ensure maximal reproducibility, only scans that utilized identical imaging parameters (field of view, scanning time and slice thickness) at baseline and 24 months were compared. To measure trabecular bone density, the reader chose identical regions of interest in the core of the vertebra chosen for baseline and follow-up analysis (Figure 1). For the measurement of cortical bone density, a region of interest was placed in the end-plates of the same vertebra. The computer software calculated the mean, SD, minimum and maximum density within the region of interest and expressed the results in Hounsfield units (HU; attenuation units typically used in CT imaging). In general, bone turnover is slow compared with changes in most other cell systems, and for this reason the primary analysis was conducted in the patients with both baseline and 24 month scans. Baseline and 24 month images were compared side by side to ensure that the reader used identically cut planes in both cases. Slice re-orientation was employed if an imaging cut plane perpendicular to the vertebral long axis could not be obtained. Since the physician interpreting the CT scans was blinded to all clinical information including binder assignment, the side by side display of images did not influence the outcome of density analysis. In a previous study of 111 adult haemodialysis patients with baseline and 1 year scans obtained using the same methods as described here, 15% of scans were re-analysed by another experienced investigator. The intra-reader agreement was 0.95 and the inter-reader agreement was 0.87 [4].



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Fig. 1. Bone tissue density measurement in regions of interest in the lower thoracic vertebral body.

 
Statistical analysis
Baseline characteristics were compared between the sevelamer and calcium carbonate groups using a Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Percentage changes in coronary and aortic calcification were assessed among patients with baseline scores of at least 30, as done in previous studies [3]. For all analyses of laboratory and EBT parameters, Wilcoxon rank sum tests were used to compare differences between treatment groups and Wilcoxon signed rank tests were used to assess changes over time within treatment group. We investigated the impact of active vitamin D usage at the midpoint of the study on the change in bone density using a linear regression model with treatment assignment (sevelamer vs calcium) as an independent variable and vitamin D usage (yes vs no) as a covariate. To investigate factors that might be associated with change in calcification, we calculated Spearman rank correlation coefficients between time-averaged laboratory variables and the changes in arterial calcification scores and bone densities. Linear regression models were used to assess for confounding attributable to imbalanced baseline demographics (age and gender) and time-averaged serum phosphorus, serum calcium, total cholesterol and iPTH. Due to the small sample size, the models were kept very simple (change regressed on treatment and one covariate at a time) and only addressed covariates for which confounding may have been clinically expected and for which reasonably complete data were available in order to avoid spurious conclusions. All probability values are two-tailed. P-values <0.05 were considered statistically significant. All analyses were conducted using SAS Version 6.12 or higher (Cary, NC).



   Results
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 Subjects and methods
 Results
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 References
 
Patient characteristics
Table 1 displays baseline demographics and medical history of the 72 patients who received treatment in the second year. These data were collected at the start of the 2 year treatment period. There were no statistically significant differences between the treatment groups at baseline. Fifty-four patients completed the study and 52 had final EBT scans. The reasons for leaving the study early were adverse clinical events (one in each group), patient desire to leave the study (two in the calcium group), kidney transplantation (three in each group), death (one in the sevelamer group and four in the calcium group) and miscellaneous other reasons (one in the sevelamer group and two in the calcium group). Body weights were stable throughout the study. At baseline, four sevelamer and three calcium patients had a history of transplantation, and two sevelamer and two calcium patients had a history of parathyroidectomy. There were three new transplants and three new parathyroidectomies during the 2 years and these patients were discontinued from the study at the occurrence.


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Table 1. Baseline characteristics of study patients

 
The doses of sevelamer and calcium carbonate were 6.9±2.6 and 4.3±1.7 g/day, respectively, during the first year of treatment. The proportion of patients using active forms of vitamin D tended to be higher in the calcium group at the start of the study (24% in the calcium vs 19% in the sevelamer patients). However, by the end of the first year of the trial, the trend was reversed, with 39% of sevelamer patients and 17% of calcium patients using vitamin D. Among all 72 patients, the average weekly dose of 1,25-dihydroxyvitamin D or its analogues increased during the first year of the study significantly in the sevelamer group 0.88 µg/week (P = 0.0449) and decreased by 0.05 µg/week in the calcium carbonate group (P = 0.7109). The most frequent dialysate calcium concentration used was 1.5 mmol/l. In the calcium carbonate group, dialysate calcium was decreased in six patients and increased in four patients over the 2 years. In the sevelamer group, dialysate calcium was increased in five patients and decreased in two patients over the 2 years. One patient on calcium carbonate and no patient on sevelamer required a calcium supplement for hypocalcaemia. The proportion of patients using lipid-lowering medications and doses was unchanged during the first year of the study but not controlled during the second year.

Biochemical results
Table 2 summarizes serum phosphorus, calcium, calcium x phosphorus product and iPTH over time. Similar trends were observed between treatment groups for all analytes except iPTH, for which patients treated with calcium carbonate were observed to have markedly lower values (P<0.001) at the 1 and 2 year follow-up time points, representing oversuppression of iPTH. A greater percentage of calcium carbonate patients experienced hypercalcaemic episodes, defined as either serum calcium >2.6 mmol/l (sevelamer 26%, calcium carbonate 54%, P = 0.0291) or serum calcium >2.8 mmol/l (sevelamer 6%, calcium carbonate 27%, P = 0.0322). The sevelamer-treated group had significantly higher alkaline phosphatase [sevelamer, median 110, interquartile range (IQR) 99–131, vs calcium, median 83, IQR 73–114, P = 0.046] and lower total cholesterol levels (sevelamer, median 145, IQR 137–163, vs calcium, median 175, IQR 157–219, P = 0.0005). In a subset of patients, we also collected data on 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, HDL cholesterol, pH and CO2. No statistically significant differences between treatment groups were observed. During the first year, there was a fall of LDL cholesterol in sevelamer patients but no further reduction during the second year.


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Table 2. Mean±SD (median) biochemical parameters over time

 
Coronary and aortic calcification scores
At baseline, calcification of the coronary arteries and aorta was severe but highly variable between subjects, with baseline coronary artery scores ranging from 0 to 6652 and the baseline aorta calcification scores ranging from 0 to 14 215. Coronary artery scores >400 convey significantly increased risk of cardiovascular events in the non-renal failure population [6]. After 1 year, there was a trend to greater increase in coronary artery calcification in the calcium group (calcium carbonate mean 219±732, median 94 vs sevelamer mean 14±633, median 0, P = 0.078) and significantly greater increase in aortic calcification in the calcium group (calcium carbonate mean 602±3126, median 257 vs sevelamer mean –702±1614, median 0, P = 0.006). The magnitude of the changes observed and the differences between treatment groups were very similar to the results for the larger groups of patients treated with calcium carbonate and sevelamer, suggesting that those who continued into the extension protocol were similar in terms of their progression of arterial calcification [5]. Table 3 summarizes baseline calcification scores as well as nominal and percentage change (in the subset with significant baseline calcification) between baseline and 24 months. There was a non-significant median increase of 37 in coronary artery calcification score in the sevelamer-treated group (P = 0.3118) vs a highly significant (P = 0.0001) median increase of 484 in the calcium-treated group (between-group P = 0.0178). For the aorta, there were similar findings, with a non-significant median change of 0 in the sevelamer-treated group (P = 0.5966) vs a highly significant (P = 0.0003) median increase of 610 in the calcium-treated group (between-group P = 0.0039). Six sevelamer- and five calcium-treated patients had baseline scores that were <30 for the coronary artery, and seven sevelamer- and four calcium-treated subjects had baseline scores that were <30 for the aorta. Excluding these patients with no or minimal calcification did not alter the magnitude or statistical significance of the results. In the subset of patients with a calcification score <30 at baseline, the median percentage changes in calcification scores were 20% for sevelamer (P = 0.1089) and 83% for calcium (P<0.0001) for the coronary arteries and –7% for sevelamer (P = 0.3755) and 66% for calcium (P<0.0001) for the aorta. The between-treatment group comparisons were statistically significant for percentage change in both coronary artery (P = 0.0310) and aortic (P = 0.0125) calcification scores. In linear regression models used to assess for confounding, only total cholesterol was associated with a modest reduction in our estimate of the sevelamer advantage with respect to change in aortic calcification.


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Table 3. Coronary and aortic agatston score at baseline and changes from baseline at 21 months

 
The majority of patients had neither aortic nor mitral valve calcification throughout the study. However, there was a small but significant increase in aortic valve and a trend towards increased mitral valve scores in the calcium-treated patients (aortic mean change 230, median 0, P = 0.03 and mitral mean change 370, median 0, P = 0.09) but not in the sevelamer patients (aortic mean change 232, median 0, P = 0.56, and mitral mean –912, median 0, P = 0.32). The between-treatment P-values were not significant.

Vertebral bone tissue density
At baseline, the bone tissue density was similar between the two treatment groups for both trabecular (sevelamer mean 162±48 HU, calcium 167±66 HU, P = NS) and cortical (sevelamer 272±55 HU, calcium 282± 80 HU, P = NS) bone. Table 4 summarizes the changes in density after 24 months of randomized treatment. Calcium treatment was associated with a significant decrease in trabecular density and a trend toward decreased cortical density. In contrast, sevelamer treatment was associated with a significant increase in trabecular density and no change in cortical density. Figure 2 displays the change and percentage change in trabecular density in patients treated with either calcium or sevelamer. A higher proportion of patients in the calcium group experienced a >10% decrease in trabecular bone density (calcium 38% vs sevelamer 4%, P = 0.0066). For cortical bone density, a slightly greater proportion of calcium-treated patients experienced a >10% decrease in cortical bone density (calcium 24% vs sevelamer 17%, P = 0.7354). In linear regression models used to assess for confounding, the estimates of sevelamer's treatment advantage with respect to changes in bone density was constant. Accounting for usage of vitamin D did not alter the effect of treatment assignment (sevelamer vs calcium) on the change in bone density. Changes in arterial calcification and changes in bone density were not significantly correlated.


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Table 4. Change (Hounsfield units) and percentage change in thoracic spine bone density by treatment

 


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Fig. 2. Change and percentage change in trabecular bone density for sevelamer (n = 21) and calcium (n = 29). The horizontal lines from bottom to top represent the 10th, 25th, 50th, 75th and 90th percentiles. The circles represent the outliers.

 
To understand possible mechanisms for why calcium treatment would be associated with vascular calcification and bone density loss, we conducted correlation analyses between the time-averaged biochemical parameters obtained at the local laboratories and the changes in coronary artery calcification, aortic calcification, trabecular density and cortical density. In the sevelamer group, change in coronary calcification was correlated with average phosphorus concentration (r = 0.70, P = 0.002). Change in aortic calcification was correlated with phosphorus (r = 0.69, P = 0.0003) and 1,25-dihydroxyvitamin D (r = –0.76, P = 0.0489) concentrations. Change in cortical density was correlated with 25-hydroxyvitamin D concentration (r = 0.65, P = 0.0425), pH (r = 0.60, P = 0.0306) and albumin concentration (r = 0.63, P = 0.0094). In the calcium group, change in coronary calcification was correlated with high sensitive C-reactive protein concentration (r = –0.38, P = 0.0438). Change in aortic calcification was correlated with phosphorus concentration (r = 0.47, P = 0.0101) and alkaline phosphatase activity (r = –0.45 P = 0.0155). Change in trabecular density was correlated with alkaline phosphatase activity (r = –0.46, P = 0.0115).



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 Abstract
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 Subjects and methods
 Results
 Discussion
 References
 
In good agreement with the 1 year result, there was a further increase in calcification of coronary arteries and the aorta in calcium carbonate-treated patients during the second year [5]. In patients with a baseline calcification score of >30, the relative increase in coronary artery and aortic calcification was constant over the 2 years of observation in the calcium carbonate-treated patients. In contrast, in sevelamer-treated patients, the coronary calcification increased non-significantly during the second year and the aortic calcification was unchanged.

Some treatments are effective under the conditions of a strict clinical trial but fail in standard clinical practice. During the second year of this study, phosphate binder therapy was used in the routine manner without pill counting, frequent patient interviews or other procedures to improve compliance and efficacy of the drug. Serum phosphorus, calcium and calcium xphosphorus product were similar between the first and second year of treatment. There was a higher iPTH in both treatment groups in the second year. However, there was a difference between the iPTH values measured at the central laboratory and the local laboratories at 1 year, indicating a difference in the reference ranges. Using the local laboratory results (higher iPTH) as a reference point, many sevelamer-treated patients had iPTH values above those suggested by the K/DOQI guidelines (150–300 pg/ml), while many of the calcium-treated patients had iPTH below the K/DOQI target [2]. Despite more liberal study procedures in the second year, there was a constant advantage of sevelamer compared with calcium carbonate in terms of vascular calcification.

Hence, calcium-based binders may contribute to tissue calcification in the setting of hyperphosphataemia [3]. Little is known of the effects of calcium-based binders on bone health. Normally, absorbed calcium would be transferred into bone or excreted by the kidney, but a depressed bone turnover makes bone less able to incorporate calcium and phosphate, leading to increased deposition in non-osseous tissues in chronic kidney disease (CKD) patients [7]. Recently, London et al. reported that arterial calcification of the carotid arteries, abdominal aorta, iliofemoral axis and legs was associated with the dose of calcium-containing phosphate binders, low iPTH and adynamic bone disease [8].

Absorbed calcium from phosphate binders has a direct suppressive effect on PTH secretion. Since the introduction of these binders and the routine use of active vitamin D analogues, low turnover bone (adynamic bone) has become as common as high turnover bone and is found in ~40% of US haemodialysis patients [9]. Recently, K/DOQI guidelines recommended limiting total calcium intake to 2 g/day, 1.5 g from the phosphate binder, in stage 5 CKD patients [2]. In dialysis patients, the current trend is to maintain dietary calcium intake equal to that of the recommended daily allowance for post-menopausal women. There is, however, a paucity of data surrounding the desirable or adequate intake of dietary calcium in ESRD patients who lack an excretory mechanism, and current recommendations are opinion based. Patients with advanced CKD have a high prevalence of osteopenia and osteoporosis and ongoing bone density loss despite treatment with calcium-based phosphate binders [10,11]

In the present study, we were interested in knowing the effect of phosphate binder therapy on bone density. Quantitative CT is precise and has the advantages of measuring trabecular and cortical bone tissue density and avoiding artefacts due to osteophytes and aortic calcification. Inverse correlation between advanced arterial calcification and bone density has been shown in osteoporotic women [12,13]. It is unknown how much such data can be extrapolated to patients with ESRD. However, a limited number of cross-sectional quantitative CT studies in CKD patients have been published [14]. Lumbar trabecular density correlates with trabecular bone volume and mineralized bone volume determined by histomorphometry of iliac crest bone biopsies [15]. Trabecular bone density is positively correlated with PTH and bone turnover, while the reverse is true for cortical bone [14]. In the present study, EBCT of thoracic vertebrae rather than the lumbar vertebrae was used for analysing the change of bone density during the 2 year period. Other investigators have confirmed a high correlation between thoracic and lumbar bone mineral density in men (r = 0.90, P<0.0001) and women (r = 0.94, P<0.0001) [16].

Our longitudinal analyses of the change in vascular calcification and bone density documented progressive vascular calcification and loss of trabecular bone density and a trend toward loss of cortical bone density in the calcium group. In contrast, in the sevelamer group, progression of vascular calcification was attenuated and trabecular and cortical bone density tended to increase. The bone loss in the calcium-treated patients occurred despite significantly lower iPTH than in the sevelamer group. PTH has been negatively correlated with bone density in previous studies of CKD patients, and low bone density is predictive of fracture in this population [11,17]. However, some investigators have documented an increased risk of fracture, particularly of the axial skeleton, in CKD patients with low PTH [18,19]. In addition to the lower iPTH in calcium-treated patients, the negative correlation between alkaline phosphatase and aortic calcification agrees with reports indicating that soft tissue calcification can be enhanced not only by hyperparathyroidism but also by hypoparathyroidism [8].

A possible explanation of our findings is that patients on sevelamer used more vitamin D than the calcium patients. However, we were unable to find a correlation between measured circulating levels of 1,25-dihydroxyvitamin D and change in bone density. Furthermore, the bone loss findings were not significantly altered when adjustments were made for use of vitamin D.

The potential influence of statins can also be excluded since the percentage of statin-treated patients remained constant in each group. Furthermore, there were no marked changes in body weight, kidney transplantations or parathyroidectomies during the 2 year study, and thus such factors probably did not play a role in explaining the results.

A limitation of this study, particularly of the bone findings, is the small sample size. Further, the bone density measurements were performed in the absence of a bone phantom. The phantom allows recalibration to prevent drift in measured density over time. However, since each individual patient was compared with himself and the scans were performed with identical imaging parameters over time, a phantom may not have been necessary to assess the intra-individual changes (changes were measured first within each patient and then between patient groups). CT does not accurately assess cortical bone thinning, bone architecture or strength. Also, we were only able to examine the lower thoracic spine. Nonetheless, this is a very common site for osteoporotic fractures and, as mentioned above, CT bone density measurements in the thoracic spine are as accurate as at the lumbar level [16,20].

In conclusion, using EBCT imaging, we demonstrated that over 2 years calcium carbonate use was associated with progressive calcification of the coronary arteries and aorta. Unlike calcium carbonate, sevelamer was not associated with progressive arterial calcification. Trabecular bone density decreased in the calcium carbonate-, but not the sevelamer-treated patients. The impact of various phosphate binders on bone density deserves further investigation in prospective studies using a variety of validated methods that measure bone density and, ideally, fracture rates.



   Acknowledgments
 
The authors appreciate the efforts of the radiologists who performed the EBCT imaging: R. Rienmüller, Graz, Austria; D. H. W. Grönemeyer, Bochum, Germany; T. Wiese, Berlin, Germany; G. Weisser, Mannheim, Germany; and S. Achenbach, Erlangen, Germany. A portion of these data was presented in abstract form at the 40th Congress of the European Renal Association European Dialysis and Transplant Association Meeting, June, 2003, Berlin, Germany.

Conflict of interest statement. J. Bommer has received consultancies and honoraria from Genzyme Inc. P. Raggi is a member of the Speakers’ bureau for Genzyme Inc. and has received research grants from Genzyme Inc. All other authors declare no conflict of interest.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 4.10.04
Accepted in revised form: 13. 4.05





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