Effect on bone biopsies

While aluminum was an effective phosphate binder, it caused osteomalacia and adynamic bone disease. Specifically, aluminum impairs mineralization of the matrix by laying down crystals that interfere with calcium deposition. In vivo data show that aluminum increases bone resorption and impairs new bone and matrix formation.

Diagnosis of aluminum-related bone disease is based on a bone biopsy that demonstrates increased aluminum staining of the bone surface (more than 15%-25%) and often adynamic bone or osteomalacia. In a cross-sectional study of long-term dialysis patients with or without stainable bone aluminum, patients with a greater degree of stainable bone aluminum were found to have low bone turnover, low bone volume, and an increase in unmineralized bone (J Lab Clin Med. 1986;107:481-487). Other studies report similar effects (J Clin Invest. 1984;73:171-181 and Kidney Int. 1981;20:375-378). 

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Recognition that aluminum has a deleterious effect on bone resulted in the widespread use of calcium-based binders. However, their use was also associated with adynamic bone disease, characterized by relatively lower parathyroid hormone (PTH) levels and decreased bone turnover. Additionally, calcium-based binders may accelerate extra-osseous calcification, as vascular calcification has been associated with increasing doses of calcium-based binders.

The effects on bone of sevelamer hydrochloride, which was developed as an alternative to calcium-based phosphate binders, have been evaluated in two studies. The first study compared the effects of calcium-based binders and sevelamer on changes in bone attenuation in the thoracic spine using electron beam CT (EBCT). One hundred and eleven patients were randomized to either sevelamer or calcium acetate; EBCT scans were done at baseline and at 52 weeks.

Compared with sevelamer, calcium-based phosphate binders resulted in decreases in both trabecular and cortical bone attenuation, a surrogate of bone mineral density. More than 30% of calcium-treated subjects had a 10% greater decrease in bone attenuation than those treated with sevelamer (J Bone Miner Res. 2005;20:764-772).

A subsequent study compared the effects of sevelamer vs. calcium carbonate on bone histomorphometry. Sixty-eight patients had bone biopsies performed at baseline and at one year. Prior to randomization, 93% of patients were treated with calcium-based binders as monotherapy; adynamic bone disease (the most prevalent histologic finding) was present in 59% of the baseline biopsies (J Am Soc Nephrol. 2008;19:405-412).

Baseline demographics and biochemical characteristics were similar between the two groups and well-controlled in the study. Following one year of treatment, the sevelamer-treated patients had lower serum calcium and higher PTH concentrations. Compared with baseline values, there were no differences between groups in mineralization or measures of bone turnover. Sevelamer, however, was shown to result in increased bone formation and improved trabecular architecture.