Oral Phosphate Binders in the Treatment of Pseudoxanthoma Elasticum

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By Joshua A. Zeichner, MD, Robin Blum, MD, and Mark Lebwohl, MD

Pseudoxanthoma elasticum (PXE) is a systemic connective tissue disorder in which the body's elastic fibers become calcified and harden. Approximately 1 in 100,000 people are affected. The disease manifests itself most prominently in the skin and blood vessels. Yellow papules develop in the skin in a cobblestone pattern, resembling "plucked chicken skin." Calcification of arteries may result in gastrointestinal bleeding, early heart disease (including heart attacks), intermittent claudication and worsening of vision.

Current treatment of PXE addresses specific problems that develop as a result of calcification. However, attention is turning towards treating the calcification process itself, and recent clinical trials have been performed using medicines that help to normalized calcium levels in the connective tissue.

Two studies were conducted at Mount Sinai Medical Center in New York to examine the reversibility of elastic fiber calcification and visible appearance of PXE. In a six patient pilot study, the investigators used aluminum hydroxide (Amphogel(r)) to pull calcium out of the tissues. The drug is a phosphate binder, which lowers the total amount of phosphate available to bind calcium in the body. Half of the patients showed significant clinical improvement of their skin, and some showed histological improvement under the microscope.

Based on these preliminary findings, a larger, double blinded placebo-controlled study was conducted. The aluminum hydroxide drug used in the pilot was discontinued by the manufacturer, so sevelamer hydrochloride (Renagel(r)), an aluminum-free oral phosphate binder, was selected as an alternative. The study was divided into two parts. For the first year, half of the subjects received real medicine and the other half received placebo. During the second year of the study, all subjects were given real medicine.

All of the patients were evaluated for changes in the skin, eyes, bones and blood work. The skin was photographed and examined for severity. Biopsies of a target spot were performed and evaluated by a pathologist for changes in calcium levels. All patients were also required to have a low calcium diet during the study.

Both the placebo and Renagel groups showed a significant decrease in clinical scores and calcification over two years, but the difference between the two groups was not significant. Improvement in the placebo group during the first year was likely due to patient education and control over dietary intake of calcium. One patient experienced clinically significant improvement in symptoms of claudication and a slight overall improvement in vascular studies. There were no statistically significant changes in vision during the study.

While Renagel did not show a statistically significant regression of skin lesions, there was a significant change seen in the Amphogel study. The difference in results between the two studies is hypothesized to be due to a change in the phosphate binder used. While Renagel is a safer medication, Amphogel is a more effective phosphate binder. Alternative phosphate binders, such as lanthanum carbonate, or higher Renagel doses could be used in future studies.

There is much promise for the future of the use of phosphate binders in PXE. Treatment with both Amphogel and Renagel led to clinical and histological improvement. Future studies must be performed to evaluate additional phosphate binders as well as different dosing regimens to locate the ideal drug for this disease.