Original investigations
Dialysis therapies
Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis

https://doi.org/10.1053/j.ajkd.2004.06.009Get rights and content

Background: Coronary artery calcification (CAC) is thought to be associated with greater cardiovascular mortality in patients with end-stage renal disease than in nonuremic persons. The purpose of the present study is to assess the effects of etidronate, a synthetic analogue of pyrophosphate, on progression of CAC score. Methods: The extent of CAC was evaluated by using multidetector spiral computed tomography. Repeated CAC score estimation was possible in 35 patients (29 men, 6 women). Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Serum osteoprotegerin (OPG) was measured by using enzyme-linked immunoassay. Serum etidronate was measured by means of the gas spectrometry technique using deuterium-labeled etidronate as internal standard. Results: Mean patient age was 63.2 ± 8.2 (SD) years, and mean duration of dialysis therapy was 7.4 ± 5.5 years. CAC score was estimated 3 times in each patient. After the second CAC score estimation, 35 patients were administered etidronate, 200 mg/d, for 14 days. This cycle was repeated 3 times every 90 days. CAC progression was significantly less pronounced during treatment with etidronate compared with the period before treatment was initiated. The median annualized absolute increase in calcified volume was 195.0 mm3 without treatment compared with −490.0 mm3 during treatment (P < 0.01). Patients were divided into 2 groups based on changes in CAC score during etidronate treatment. Responders (n = 26) were patients whose CAC score decreased during therapy, and nonresponders (n = 9) were patients whose CAC score increased, even after etidronate therapy. Serum C-reactive protein values (0.18 ± 0.13 mg/dL) in the responder group were greater than those (0.14 ± 0.08 mg/dL) in the nonresponder group (P = 0.013). Serum OPG levels decreased significantly during etidronate therapy (256.8 ± 93.8 versus 245.0 ± 83.0 pg/mL; P = 0.0161). Etidronate was well tolerated during the study. BMD values during etidronate therapy were not significantly changed from 0.941 ± 0.125 to 0.968 ± 0.246 g/cm2. Conclusion: Results of the present study suggest that the extent of CAC may be suppressed by etidronate in association with a reduction in chronic inflammatory responses. They also suggest that a decrease in serum OPG concentrations by means of etidronate may be associated with changes in vascular calcification in dialysis patients.

Section snippets

Subjects

Of patients undergoing regular hemodialysis at the Dialysis Unit of Takeda General Hospital (Fukushima, Japan), 53 patients agreed to have their CAC score estimated. We excluded 6 patients with obvious acute inflammation and 2 patients who did not comply with their drug therapy. Two patients did not comply adequately with the etidronate regimen. Eight patients were excluded from the study for the following reasons: refusal of follow-up MDCT, 3 patients; transfer to another dialysis unit, 3

Clinical course of control group

Table 1 lists clinical courses of patients without etidronate therapy. The MDCT was performed twice, with a mean interscan period of 388 ± 21 days. This interval between the first and second MDCT scans was compatible with those in the study group (374 days). Median CAC score increased from 1,303 mm3 (range, 231 to 3,133 mm3) to 1,462 mm3 (range, 220 to 3,450 mm3). No significant changes were observed in serum levels of Ca, P, and iPTH (8.8 ± 1.0 versus 8.8 ± 0.9 mg/dL [2.20 ± 0.25 versus 2.20 ±

Discussion

Many investigators were able to establish that atherogenic vascular calcification in patients without ESRD is caused by an active process resembling osteogenesis in bone.17 In this process, vascular smooth muscle cells transform into phenotypically distinct cells capable of calcification in vitro.18 These modified vascular smooth muscle cells facilitate mineralization in vitro by forming nodules similar to those produced by osteoblasts, producing bone-associated proteins, and forming matrix

Acknowledgment

The authors thank Hiroyuki Ashikaga for assessment of CAC score; Masahiro Haga for blood sampling; Keita Matsushita (Sumitomo Pharmaceutical Co, Tokyo, Japan) for help in serum etidronate level measurement; and John P McCormick, PhD, for reviewing the manuscript.

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    Supported in part by a grant from the Renal Osteodystrophy Foundation in Japan.

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