Original Investigation
Pathogenesis and Treatment of Kidney Disease
Effect of Alendronate on Vascular Calcification in CKD Stages 3 and 4: A Pilot Randomized Controlled Trial

https://doi.org/10.1053/j.ajkd.2009.12.039Get rights and content

Background

Vascular calcification contributes to cardiovascular disease in patients with chronic kidney disease (CKD). Few studies have addressed interventions to decrease vascular calcification; however, experimental studies report benefits of bisphosphonates. Recent studies of hemodialysis patients also suggest benefits of bisphosphonates on vascular calcification; however, no study exists in nondialysis patients with CKD.

Study Design

We conducted a randomized controlled trial to determine the effect of bisphosphonates on vascular calcification in patients with CKD.

Setting & Participants

51 patients with CKD stages 3-4 were recruited from a hospital outpatient setting; 50 were treated with study medication.

Interventions

Patients were randomly assigned to either alendronate, 70 mg (n = 25), or matching placebo (n = 25), administered weekly.

Outcomes

The primary outcome was change in aortic vascular calcification after 18 months. Secondary outcomes included superficial femoral artery vascular calcification, arterial compliance, bone mineral density (BMD), renal function, and serum markers of mineral metabolism.

Measurements

At baseline and 12 and 18 months, computed tomography, pulse wave velocity using SphygmoCor (AtCor Medical, PWV Inc, www.atcormedical.com), and dual-energy x-ray absorptiometry were performed to measure vascular calcification, arterial compliance, and BMD, respectively. Analysis was by intention to treat, with a random-effect linear regression model to assess differences.

Results

46 patients completed the study (24 alendronate, 22 placebo); baseline mean age was 63.1 ± 1.8 years, estimated glomerular filtration rate was 34.5 ± 1.4 mL/min/1.73 m2, 59% had diabetes, and 65% were men. 91% had aortic vascular calcification at the start and 78% showed progression. At 18 months, there was no difference in vascular calcification progression with alendronate compared with placebo (adjusted difference, −24.2 Hounsfield units [95% CI, −77.0 to 28.6]; P = 0.4). There was an increase in lumbar spine BMD (T score difference, +0.3 [95% CI, 0.03-0.6]; P = 0.04) and a trend toward better pulse wave velocity (−1 m/s [95% CI, −2.1 to 0.1]; P = 0.07) with alendronate. Femoral BMD was similar between groups. There was a nonsignificant decrease in kidney function in patients on alendronate therapy compared with placebo (−1.2 mL/min/1.73 m2 [95% CI, −4.0 to 1.7]).

Limitations

Small sample size and baseline differences, especially with aortic vascular calcification, may have diminished any potential difference between groups.

Conclusions

Unlike previous studies of hemodialysis patients, alendronate did not decrease the progression of vascular calcification compared with placebo in patients with CKD during 18 months.

Section snippets

Study Participants

Fifty-one patients were recruited between January and June 2007 from outpatient clinics and private consulting rooms by nephrologists at Monash Medical Centre, Clayton, Australia (Fig 1). Inclusion criteria were age 18-80 years, patients willing to give informed consent, and those with decreased glomerular filtration rate (GFR) of 20-60 mL/min/1.73 m2, estimated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation.29 In addition, because alendronate is not

Characteristics of Study Groups

Fifty-one patients were recruited and randomly assigned in this study (Fig 1). One patient who withdrew after randomization and initial investigations, but before the start of study medication, was replaced to maintain treatment allocation in a 1:1 randomization so that 25 patients were allocated to alendronate and 25 were allocated to placebo. During the study period, 2 patients (1 in each group) died of conditions unrelated to the study and 2 were lost to follow-up (both in the placebo group)

Discussion

The present study is the first randomized trial to assess the efficacy of bisphosphonates on decreasing the progression of vascular calcification in the stage 3-4 CKD population. Despite experimental evidence and some clinical studies suggesting that bisphosphonates, potent inhibitors of bone resorption, may decrease the progression of extraosseous calcification and potentially inhibit atherosclerosis, we found no significant difference in the progression of aortic or superficial femoral artery

Acknowledgements

We acknowledge Kate Lyttle (Merck & Co Inc, Australia) for assistance and support with provision of the study medication (alendronate and placebo) and Dr Rory Wolfe (Monash University) for expert statistical advice.

Support: Dr Toussaint is supported by a grant from the National Health and Medical Research Council of Australia. Further information on funding sources is listed in the financial disclosure.

Financial Disclosure: Merck & Co Inc, which markets alendronate, provided support through

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      Clinical studies evaluating vascular outcomes in patients with CKD are scanty. Although the first-generation bisphosphonate etidronate markedly reduced the progression of vascular calcification in patients with CKD,107 recent generation nitrogen-containing bisphosphonates alendronate and ibandronate demonstrated either improved or unchanged vascular outcomes.79,105,106 In a recent randomized controlled trial, therapy with either alendronate or denosumab for 1 year did not affect indices of vascular health (including vascular calcification scores) in patients on dialysis.79

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    Originally published online as doi:10.1053/j.ajkd.2009.12.039 on March 29, 2010.

    Trial registration: www.ClinicalTrials.gov; study number: NCT00395382

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