A Comparison of Sevelamer Hydrochloride with Calcium Acetate on Biomarkers of Bone Turnover in Hemodialysis Patients

Abstract

Objective. To evaluate the influence of sevelamer hydrochloride and calcium acetate on biomarkers of bone turnover in patients with hyperphosphatemia receiving hemodialysis. Methods. In this prospective, open-label, randomized, active-controlled study, 70 patients (38 men and 32 women) with hyperphosphatemia (serum phosphorus level >6.0 mg/dL) underwent a two-week washout period and were randomly selected to receive sevelamer hydrochloride (n = 37) or calcium acetate (n = 33) for eight weeks. Changes in serum levels of intact parathyroid hormone (iPTH), alkaline phosphatase (Alk-P), phosphorus, and calcium were measured and compared. Results. After eight weeks of treatment, calcium acetate lowered iPTH levels significantly more than sevelamer hydrochloride did (−178.0 vs. −69.0 pg/mL, p = 0.0019). Levels of Alk-P were significantly elevated in patients given sevelamer hydrochloride compared with levels in those given calcium acetate treatment (24.09 vs. 7.45 U/L, p = 0.0014). Changes in serum phosphorus levels did not differ between sevelamer hydrochloride (−1.93 mg/dL) and calcium acetate (−2.5 mg/dL) at the end of the study (p = 0.0514). Changes in the calcium and phosphorous product did not significantly differ between the sevelamer-hydrochloride group (−18.06 mg²/dL²) and the calcium-acetate group (−19.05 mg²/dL², p = 0.6764). Fifteen patients (45.5%) treated with calcium acetate had hypercalcemia (serum-adjusted calcium level >10.5 mg/dL); the rate was significantly higher than that of patients treated with sevelamer (five [13.5%] of 37, p = 0.0039). Conclusion. Treatment with sevelamer hydrochloride had the advantage of maintaining stable iPTH levels and elevating Alk-P levels while lowering serum phosphorus levels and calcium-phosphorous product.

Keywords:

• sevelamer hydrochloride
• calcium acetate
• hyperphosphatemia
• bone turnover
• hemodialysis

INTRODUCTION

Hyperphosphatemia is a common complication of end-stage renal disease. In addition, hyperphosphatemia and a level of high calcium-phosphorus product have been correlated with high rates of cardiovascular disease and mortality in patients receiving long-term dialysis.[1–3] Moreover, hyperphosphatemia stimulates the secretion of parathyroid hormone (PTH) and results in secondary hyperparathyroidism and further renal osteodystrophy. Therefore, controlling serum levels of phosphorus and of calcium-phosphorus product is critically important in patients receiving long-term dialysis.

The phosphate binders in popular use today are based on calcium or aluminum, which are associated with a variety of adverse effects. Because the long-term administration of aluminum-based phosphate binders may lead to aluminum intoxication, calcium-based phosphate binders are preferred. However, calcium-based binders increase the risk of hypercalcemia events. Both calcium salts per se and sequential hypercalcemia may decrease bone turnover.[4],[5] Therefore, calcium-based phosphate binders are used to decrease serum phosphorus concentrations and prevent renal osteodystrophy. However, such binders may induce other metabolic bone diseases.

Sevelamer hydrochloride is a calcium- and aluminum-free polycationic polymer that reduces phosphorus absorption from the gastrointestinal tracts by binding dietary phosphorus. Studies have shown that sevelamer hydrochloride is effective in controlling serum levels of phosphorus and calcium-phosphorus product.[6–8] Furthermore, sevelamer hydrochloride significantly decreases the risk of hypercalcemia compared with calcium-based phosphate binders.[6–9] However, little is known about its influence on bone turnover. Therefore, this study was designed to evaluate the influence of sevelamer hydrochloride and calcium acetate on biomarkers of bone turnover—namely, levels of serum intact PTH (iPTH) and alkaline phosphatase (Alk-P)—in patients with hyperphosphatemia who were undergoing hemodialysis. In addition, the efficacy of these drugs in controlling serum levels of phosphorus, calcium, and calcium-phosphorus product was evaluated.

METHODS

Study Design

The authors' ethical committee approved this prospective, open-label, randomized, active-controlled trial, and all patients signed informed consent before entering the study.

Patients who met the inclusion criteria and none of the exclusion criteria were eligible for the study. Only patients who developed clinically significant hyperphosphatemia during the washout period were eligible for treatment randomization. The inclusion criteria were hyperphosphatemia (serum phosphorus level >6.0 mg/dL) during the two-week washout period, an age of 20 years or older, hemodialysis three times per week for at least three months, stable doses of calcium-based phosphate binders for at least one month, and stable doses of a vitamin D replacement for at least one month if this therapy was given. During the two-week washout period, all kinds of phosphate binders were discontinued in all patients. The main exclusion criteria were an adjusted serum calcium level of greater than 11 mg/dL during the washout period or any of the following laboratory abnormalities on the screening blood test: hemoglobin <8.0 g/dL or ALT or AST ≥3 times the upper limit of normal.

After the washout period, patients with hyperphosphatemia were randomly selected to receive either sevelamer hydrochloride 400 mg (Renagal tablet) or calcium acetate 667 mg (Caphos tablet) for eight weeks. Patients maintained their regular dialysis schedule and normal dietary habits throughout the study.

Starting dosages depended on the degree of hyperphosphatemia, as follows: >6.0 to <7.5 mg/dL, two tablets of sevelamer or one tablet of calcium acetate three times daily; ≥7.5 to <9.0 mg/dL, three tablets of sevelamer or two tablets of calcium acetate three times daily; and ≥9.0 mg/dL, four tablets of sevelamer or three tablets of calcium acetate three times daily. Both drugs were taken with a meal. The dose was titrated every two weeks as necessary to achieve a serum phosphorus level of 3.5–6.0 mg/dL. The largest daily dose was sevelamer hydrochloride or calcium acetate 12 g. If the serum calcium level increased above 11.0 mg/dL, the dose of calcium acetate was reduced by one to three tablets per meal to achieve a level below 11.0 mg/dL. Compliance was assessed by counting the remaining tablets. Patients were prohibited from consuming antacids containing aluminum or magnesium during the study. For patients on vitamin D replacement therapy, the investigator maintained the original dose recorded at the start of the study unless significant hypercalcemia developed. In this situation, vitamin D was reduced or stopped according to the level of hypercalcemia.

Outcome Measures

Demographic and baseline characteristics were recorded. Serum levels of iPTH and Alk-P were measured and compared between treatment groups for changes between baseline and end of study. Serum iPTH levels were measured using the immunometric, Immulite^® 2000 assay. Serum Alk-P levels were determined with the Synchron LX (Beckman Coulter, Fullerton, California, USA). In addition, changes in serum levels of phosphorus, calcium (adjusted), and calcium-phosphorus product were compared.

Safety Evaluation

Safety was evaluated on the basis of adverse events, changes in laboratory values (chemistry profile, hematology profile), changes in vital signs (blood pressure, pulse rate), and changes in physical examinations. An adverse event was defined as an unfavorable medical occurrence, including disease, the worsening of a preexistent medical condition, or any sign or symptom without a specific medical diagnosis.

Statistical Methods

All statistical analyses were based on two-sided hypothesis testing with a significance level of p < 0.05. Sevelamer hydrochloride was considered equivalent to calcium acetate if the null hypothesis was rejected at a 5% level of significance.

Data pertaining to demographics and baseline characteristics were summarized. Balance between the treatment groups was tested by using the Fisher exact test for categorical variables and an analysis variance (ANOVA) for continuous measures. For efficacy evaluation, mean changes from baseline were statistically analyzed. The mean and 95% confidence interval of the change was computed in each treatment group, and the difference between groups was examined by means of an analysis of covariance (ANCOVA) with baseline value and site location as the covariates. Discrete variables (i.e., response to treatment) were analyzed by using the Fisher exact test. For iPTH levels, descriptive statistics including median and inter-quartile were presented. A Wilcoxon signed rank test was used to assess the change in iPTH levels.

RESULTS

Over four months in 2002, 106 subjects were initially evaluated. Seventy-three patients who met all trial criteria were randomly assigned to the treatment phase: 37 given sevelamer hydrochloride and 36 given calcium acetate. Of the 73 patients, 63 patients completed the study. The most common reason for discontinuation was withdrawal of consent. In the sevelamer hydrochloride group, four patients discontinued due to consent withdrawal, investigator judgment, or violation of the protocol. In calcium acetate group, six patients discontinued due to consent withdrawal or adverse event. Three patients who did not have post-baseline efficacy data were excluded from the efficacy analysis. Therefore the intent-to-treat population comprised 70 patients: 37 in the sevelamer-hydrochloride group and 33 in the calcium-acetate group.

Baseline Demographic and Background Characteristics

Table 1 summarizes the demographic and background data. The patients were 38 (54.3%) men and 32 (45.7%) women with a mean age of 48.9 years (range, 20–73 years). Primary causes of their end-stage renal disease were hypertension (30.0%), diabetes (11.4%), polycystic kidney disease (2.9%), and others (55.7%). Previous phosphate binder usage included calcium carbonate (55.7%) and calcium acetate (44.3%). Four patients (5.7%) had previously undergone parathyroidectomy. None of the patients received calcimimetics treatment during the study period. The mean duration of dialysis was 7.3 years (range: <1–22 years), and the mean Kt/V was 1.5 (range: 0.93–3.46). In 55 patients (78.6%), the initial calcium dialysate level was 3.0 mEq/L, and 63 (90%) had an initial calcium dialysate level of 3.0 mEq/L or less. Baseline demographics did not significantly differ between the treatment groups. In the intent-to-treat population, the overall mean actual daily dose for sevelamer hydrochloride was 4.5 ± 1.3 grams/day. The overall mean actual daily dose for calcium acetate was 3.8 ± 1.6 grams/day.

Table 1 Baseline demographic and background characteristics

Characteristic	All group (N = 70)	Sevelamer (N = 37)	Calcium acetate (N = 33)	p value
Sex
Male	38	21	17	0.651
Female	32	16	16
Age (years)	48.9 ± 11.5	47.6 ± 11.9	50.4 ± 10.9	0.260
Weight (kg)	58.2 ± 9.6	59.7 ± 10.4	56.6 ± 8.5	0.238
Primary cause of ESRD
Hypertension	21	11	10	0.810
Diabetes nephropathy	8	3	5
Polycystic kidneys	2	1	1
Others (including CGN)	39	22	17
Dialysis duration (years)	7.3 ± 5.5	7.3 ± 6.1	7.4 ± 4.8	0.783
Type of phosphate binders
Calcium carbonate	39	19	20	0.556
Calcium acetate	31	18	13
Parathyroidectomy
No	66	35	31	0.947
Yes	4	2	2
Kt/V	1.5 ± 0.4	1.6 ± 0.5	1.4 ± 0.2	0.124

*Mean ± S.D.

Abbreviations: ESRD = End-stage renal disease; CGN: Chronic glomerulonephritis.

Levels of iPTH

Figure 1 summarizes the changes in total iPTH levels. Median baseline serum iPTH levels were 330.0 pg/mL for the sevelamer-hydrochloride group and 452.0 pg/mL for the calcium-acetate group (p = 0.6394). By the end of treatment, median levels were 250.0 and 195.0 pg/mL (p = 0.1607) for the sevelamer-hydrochloride and calcium-acetate groups, respectively. Median changes over the eight weeks of treatment were −69.0 pg/mL (interquartile, −138.6 to 30.6 pg/mL) for sevelamer hydrochloride and −178.0 pg/mL (interquartile, −235.0 to −99.0 pg/mL) for calcium acetate (p = 0.0019). At the end of study, the treatment difference was significant, with sevelamer hydrochloride affecting iPTH levels less than calcium acetate did.

Figure 1 Serum intact parathyroid hormone (iPTH) level (Median, 25^th and 75^th percentile).

Levels of Alk-P

Figure 2 summarizes the mean changes in serum Alk-P levels. After the two-week washout period, mean serum Alk-P levels were 63.98 U/L for the sevelamer-hydrochloride group and 57.95 U/L for the calcium-acetate group (p = 0.3457). After eight weeks of treatment, mean levels were 88.23 U/L for the sevelamer-hydrochloride group and 64.53 U/L for the calcium-acetate group (p = 0.0097). Overall, the mean increment of serum Alk-P level over eight weeks of treatment was 24.09 U/L (95% confidence interval, 15.28–32.89 U/L) and 7.45 U/L (95% confidence interval, −2.15–17.05 U/L) for the sevelamer-hydrochloride and calcium-acetate groups, respectively (p = 0.0014). At the end of study, changes in serum Alk-P levels were significantly greater with sevelamer hydrochloride than with calcium acetate.

Figure 2 Serum alkaline phosphatase (Alk-P) level (mean ± SE).

Serum Phosphorus Levels

Figure 3 summarizes the mean changes in serum phosphorus levels. After the two-week washout, mean serum phosphorus levels increased to 8.09 mg/dL in the sevelamer-hydrochloride group and 8.11 mg/dL in the calcium-acetate group (p = 0.9571). After the eight-week treatment, the mean levels were 5.94 mg/dL for the sevelamer-hydrochloride group and 5.38 mg/dL for the calcium-acetate group (p = 0.0504). Overall, the mean decrease in serum phosphorus level over eight weeks of treatment was 1.93 mg/dL (95% confidence interval, 1.43–2.44 mg/dL) for sevelamer hydrochloride and 2.5 mg/dL (95% confidence interval, 1.95–3.05 mg/dL) for calcium acetate (p = 0.0514). At the end of treatment, 21 patients in the sevelamer hydrochloride group (56.8%) and 25 in the calcium-acetate group (75.8%) achieved the serum phosphorus target (3.5–6.0 mg/dL, p = 0.1311).

Figure 3 Serum phosphorus level (mean ± SE).

Levels of Calcium and Phosphorus Product

Figure 4 summarizes the mean changes in calcium and phosphorus product (Ca × P) by treatment. After washout, mean baseline levels were 71.79 mg²/dL² for sevelamer hydrochloride and 72.41 mg²/dL² for calcium acetate (p = 0.8717). By the end of treatment, the mean Ca × P levels were 53.34 mg²/dL² for sevelamer hydrochloride and 52.49 mg²/dL² for calcium acetate (p = 0.7405). Mean changes in the Ca × P level over eight weeks of treatment were −18.06 mg²/dL² (95% confidence interval, −22.28 to −13.83 mg²/dL²) for sevelamer hydrochloride and −19.05 mg²/dL² (95% confidence interval, −23.63 to −14.47 mg²/dL²) for calcium acetate (p = 0.6764).

Figure 4 Serum calcium × phosphorus (Ca × P) level (mean ± SE).

Serum Calcium Levels

Figure 5 summarizes the mean changes in adjusted serum calcium (calcium_[adj]) level. After washout, the mean baseline serum calcium_[adj] levels were 8.91 and 8.99 mg/dL for the sevelamer hydrochloride and calcium acetate groups, respectively (p = 0.7718). After eight weeks of treatment, mean calcium_[adj] levels were 9.11 mg/dL for sevelamer hydrochloride and 9.86 mg/dL for calcium acetate (p = 0.0009). Overall, the mean change in serum calcium_[adj] levels over the eight weeks of treatment was 0.12 mg/dL (95% confidence interval, −0.17–0.40 mg/dL) for the sevelamer-hydrochloride group and 0.82 mg/dL (95% confidence interval, 0.51–1.13 mg/dL) for the calcium-acetate group (p < 0.0001).

Figure 5 Serum calcium_[adj] level (mean ± SE).

Fifteen patients (45.5%) treated with calcium acetate had hypercalcemia (serum calcium_[adj] level >10.5 mg/dL). The rate was significantly higher than that of patients treated with sevelamer hydrochloride (5 of 37 [13.5%], p = 0.0039).

Safety Evaluation

Sevelamer hydrochloride was well tolerated by most of the study patients. The incidence of adverse events was found to be similar between sevelamer hydrochloride and calcium acetate groups. There were two serious adverse events reported in the calcium acetate group. Neither of these two serious adverse events was judged to be related to study drug. Gastrointestinal side effect was noted in 17 patients with sevelamer hydrochloride treatment (45.9%) and 11 patients with calcium acetate treatment (33.3%) (p = 0.282).

DISCUSSION

Binders such as sevelamer hydrochloride, lanthanum salts, and iron salts have been developed to eliminate undesirable adverse events caused by calcium- or aluminum-based phosphate binders. In this study, sevelamer hydrochloride effectively reduced serum levels of phosphorus and calcium-phosphorus products. Fewer patients in the sevelamer-hydrochloride group than in the calcium-acetate group had hypercalcemia (serum calcium level >10.5 mg/dL; 13.5% vs. 45.5%, p = 0.0039).

Previous studies have demonstrated that iPTH and Alk-P can be used for the noninvasive diagnosis of low-turnover renal osteodystrophy in patients receiving hemodialysis, and that tests of these biomarkers are less costly than other alternatives.[10–12] Low iPTH and Alk-P levels often reflect low bone turnover and a reduced capacity to handle a calcium load.[10],[13],[14] Hence, in this situation, patients with hypercalcemia may be prone to induce cardiovascular calcification. Bran et al.[6] found that vascular calcification was correlated with low levels of PTH in patients treated with calcium salts. In addition, relative hypoparathyroidism has been associated with an increased mortality rate in patients receiving hemodialysis.[15],[16]

In this study, serum iPTH levels decreased significantly more with calcium acetate than with sevelamer hydrochloride after eight weeks of treatment (p = 0.0019). In addition, serum Alk-P levels were elevated significantly more after sevelamer-hydrochloride treatment than after calcium-acetate treatment (p = 0.0014). After eight weeks of treatment, the mean calcium_[adj] levels of patient treated with sevelamer hydrochloride were significantly lower than those treated with calcium acetate (p = 0.0009). A lower serum calcium level may enhance bone turnover rate.[17] It may be the reason that the serum Alk-P levels were elevated significantly more after sevelamer-hydrochloride treatment than after calcium-acetate treatment. In particular, sevelamer hydrochloride apparently had the advantage of maintaining stable iPTH levels and elevating Alk-P levels while lowering serum phosphorus levels. Compared with calcium acetate, sevelamer hydrochloride may offer the benefit of lower serum calcium levels, thus decreasing the risk of cardiovascular calcification.

Cardiovascular disease contributes to the high mortality rate of patients receiving long-term dialysis.[18] Calcium-based phosphate binders are often used to control serum phosphorus levels to prevent cardiovascular calcification and cardiovascular disease. However, calcium-based phosphate binders increase the risk of hypercalcemia and induce low bone turnover, a condition that may progress to excessive cardiovascular calcification. Studies have proved that using calcium-based phosphate binders resulted in more rapid cardiovascular calcification than sevelamer hydrochloride.[6],[7],[19],[20] By controlling the serum phosphorus level, decreasing rates of hypercalcemia, and improving low bone turnover, sevelamer hydrochloride may help slow the progression of cardiovascular calcification. Moreover, Collins et al.[21] reported that the likelihood of hospitalization was 50% lower in patients treated with sevelamer hydrochloride than in other patients. To the authors' knowledge, there is no long-term study comparing mortality rates between sevelamer hydrochloride and calcium-based phosphate binders. These studies may be as long as five years in the future.

There are several limitations of this study. First, a bone biopsy was not performed to measure the status of bone turnover before and after sevelamer hydrochloride or calcium acetate treatment. Second, the sample size was insufficient, and treatment duration was limited. It may be not long enough to assess the effects of sevelamer hydrochloride or calcium acetate on the rate of bone turnover. Additional study will be required to measure the actual change of bone turnover status directly after long-term sevelamer hydrochloride and calcium-based phosphate binder.

In conclusion, sevelamer hydrochloride effectively reduced serum levels of phosphorus and calcium-phosphorus products, resulting in fewer hypercalcemic events in patients receiving hemodialysis than calcium acetate. Treatment with sevelamer hydrochloride had the advantage of maintaining stable iPTH levels and elevating Alk-P levels while lowering serum phosphorus levels. These advantages of sevelamer hydrochloride may help slow the progression of cardiovascular calcification.

ACKNOWLEDGMENT

The authors would like to thank Chugai Pharma Taiwan Ltd. for providing the sevelamer hydrochloride tablets for this study.