Phosphate Binders: New Study Raises Questions about Safety and Efficacy

Weaver, Janelle

doi: 10.1097/01.NEP.0000419364.97453.43

A pilot clinical trial of phosphate binders in patients with chronic kidney disease (CKD) has generated some unexpected findings, but experts caution that more data are needed before firm conclusions can be drawn. The results were published in the Journal of the American Society of Nephrology (JASN; 2012;23:1407–1415).

“This is the first placebo-controlled trial with phosphate binders that's long-term” in patients with chronic kidney disease, said lead author Geoffrey A. Block, MD, Director of Clinical Research at Denver Nephrology. “What we show is that there's certainly the possibility of harm associated with these phosphate binders.”

As kidney function declines, serum phosphorus levels increase, potentially putting patients at risk for cardiovascular events and even death. Beyond diet and high-efficiency dialysis procedures, phosphate binders are one strategy for controlling serum phosphorus levels in these patients.

Phosphate binders are approved for use in individuals with end-stage renal disease but not in patients with non-dialysis chronic kidney disease. There has been a lack of placebo-controlled, randomized trials examining whether phosphate binders reduce the risk of clinically relevant outcomes, in part because of ethical concerns about the potential dangers of not treating dialysis patients who have high serum phosphorus levels and are assigned to the placebo group.

Two observational studies in dialysis patients reported conflicting conclusions regarding the efficacy of these agents in reducing mortality risk (Isakova T et al: J Am Soc Nephrol 2009;20:388–396; Winkelmayer WC et al: Clin J Am Soc Nephrol 2011;6:175–183).

In the new prospective trial, Dr. Block and his collaborators examined whether phosphate binders are safe and effective in patients with moderate to advanced chronic kidney disease, sidestepping ethical concerns by focusing on individuals with normal or near-normal serum phosphorus concentrations.

Although the phosphate binders were effective at reducing urine phosphorus excretion, the drugs also increased vascular calcification.

“Our study really supports the need and demand for placebo-controlled trials if you're going to establish outcomes associated with phosphate binders,” Dr. Block said in a phone interview.

“It really should result in a change in practice pattern around the world with regard to the provision of calcium as a phosphate binder in patients with chronic kidney disease. I just don't think our data can support the continued practice pattern that is prevalent right now.”

The research was funded by Shire, Fresenius NA, Genzyme, Denver Nephrologists, Novartis, and DaVita.

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‘Most Surprising Finding’

In the double-blind, nine-month-long study, 148 patients with Stage 3 or 4 chronic kidney disease who were recruited at a single center between February 2009 and September 2010 were randomly assigned to groups receiving placebo or one of three different phosphate binders—calcium acetate, lanthanum carbonate, or sevelamer carbonate.

The phosphate binders decreased mean 24-hour urine phosphorus by 22%. The decline in serum phosphorus levels—although significantly different from placebo—was modest.

The researchers did not standardize the time of day at which serum phosphorus was measured, and this could partially explain the small effects observed. Moreover, serum phosphorus fluctuates when it is measured in a non-fasted state, as in this study. The results indicate that serum phosphorus levels may not accurately reflect phosphate binder efficacy or adherence in this patient population.

While parathyroid hormone (PTH) levels increased by 21% in patients on placebo, concentrations remained stable in patients receiving phosphate binders. PTH is a major regulator of serum phosphorus, and high serum phosphorus levels contribute to the development of secondary hyperparathyroidism and bone-related complications.

However, therapy did not significantly affect plasma levels of C-terminal fibroblast growth factor 23 (FGF23)—another major regulator of renal phosphate excretion. FGF23 levels are associated with impaired kidney function and mortality.

“This was probably the most surprising finding,” said Dr. Block, who expected that a reduction in urinary phosphorus excretion would be associated with a change in FGF23.

“It's likely that that's because C-terminal is probably not the best assay to be using for serial measurements over time. That's an important conclusion of our study—if you want to look at FGF23 serially over time, it really looks as if you should study intact FGF23.”

Of most concern, treatment with phosphate binders increased vascular calcification. Among 81 patients with a nonzero baseline calcium score, therapy resulted in an increase in median annualized percent change in calcium volume scores for the coronary artery and abdominal aorta.

Twenty of 52 (38%) patients treated with a phosphate binder experienced progression of coronary artery calcification, compared with five of 29 (17%) placebo-treated patients.

Meanwhile, phosphate binders had a positive effect on bone mineral density. These effects were most pronounced with calcium acetate treatment.

Because progression of vascular calcification resulted from treatment with calcium- and non-calcium-containing phosphate binders, it's possible that both types of phosphate binders enhance the availability of free intestinal calcium, resulting in a positive calcium balance.

“This is a very important study because it highlights how complicated mineral metabolism and phosphorus metabolism is in terms of patient outcome,” said Stuart M. Sprague, DO, Chief of the Division of Nephrology and Hypertension at NorthShore University HealthSystem in Illinois.

“Our understanding is somewhat limited, and it's a much more complicated pathophysiological process than we appreciated.”

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Uncertain Outcomes

The strengths of the study include good adherence and the double-blind, placebo-controlled, randomized design, said Dr. Sprague, who was not involved in the research. But it was not designed to be definitive, he cautioned.

“We really have to look at this study as a preliminary, hypothesis-generating study. I don't think we can take any hard conclusions from this study,” he said in a phone interview.

“Future studies should be designed to look at the different classes of phosphate binders separately and their effect on hard outcome.”

Comparing all treatment groups together is a major problem, agreed Tilman B. Drüeke, MD, Research Director Emeritus at INSERM, the French National Institute of Health and Medical Research, who co-authored an accompanying JASN editorial (2012;23:1277–1280).

“These binders have very different metabolic effects, so I think it's not very reasonable to lump these three together and compare all of them to placebo,” he said, adding that the duration of the study was too short and the sample size too small to examine changes in hard patient outcomes associated with specific phosphate binders.

“The conclusion about vascular calcification is unacceptable to me and my colleague,” Dr. Drüeke said in a phone interview.

Another limitation of the study was that about 80% of the patients were Caucasian, said Jason R. Stubbs, MD, Assistant Professor of Nephrology at the University of Kansas Medical Center, who was not involved in the study.

“When you look at the chronic kidney disease population as a whole in the United States, you have a large percentage of African-Americans. It's hard to say whether the findings are completely generalizable to the population as a whole,” he said in a phone interview.

“This should be validated in a multicenter trial that would include a larger percentage of African-American patients.”

Moreover, the ability to generalize the findings to other geographic regions is limited because patients were recruited at a single center in Denver, Dr. Stubbs said. The findings cannot be applied to patients on dialysis, he added. “You'd really have to do separate studies to look at that population.”

Follow-up research is necessary to address these issues, as well as the basic physiology of communication among the intestine, kidney, and bone when there are fluctuations in phosphorus, Dr. Stubbs said.

But in the meantime, the importance of the study is clear: “It begins to call into question the use of phosphate binders and the development of phosphate binders for lowering serum phosphorus, at least in the setting of chronic kidney disease,” he said.

© 2012 Lippincott Williams & Wilkins, Inc.