Effects of Phosphate Binders on Bone

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Several studies have evaluated the effects of lanthanum on bone. Lanthanum is the most extensively studied phosphate binder with regard to potential toxicity. The effects of lanthanum compared with calcium-based binders on the development of renal osteodystrophy were determined following both one and two years of treatment. Bone biopsies were performed at baseline and one year in two studies and at baseline, one, and two years in another.

All studies demonstrated that lanthanum did not result in osteomalacia or adynamic bone disease. In fact, the number of patients who had adynamic bone disease increased after one year (20% at baseline to 30% at one year) in the calcium-treated subjects. Conversely, the percentage of patients who had low bone turnover after receiving lanthanum was lower (36% to 18%) (Kidney Int. Suppl. 2003;85:S73-S78). Additional research revealed that lanthanum showed greater improvement, as compared with calcium, in osteoblast activity and overall measures of bone turnover (Clin Nephrol. 2005;64:428-437).

The authors of both one-year studies argue that looking only at the type of renal osteodystrophy at one year may underestimate the potential improvements in bone with lanthanum over time.  In the two-year study, the percentage of patients who showed improvement in bone turnover after one year of lanthanum therapy was significantly higher than in the standard therapy group as measured by activation frequency (52.0% vs. 23.3%) and bone formation rate (41.9% vs. 15.6%).

After two years, a larger number of patients in the lanthanum group showed improvement or no change, but this did not reach statistical significance. The percentage of patients with increased bone volume was significantly higher in the two-year lanthanum group compared with those who received standard therapy (Clin Nephrol. 2008;70:284-295).

Fibroblast growth factor-23

The preceding data suggest that phosphate binders do not uniformly affect bone histology, and treatment of hyperphosphatemia does not reverse renal osteodystrophy. In recent years, researchers have identified fibroblast growth factor-23 (FGF23), a hormone that is secreted by the osteoclast and regulates phosphorus and vitamin D metabolism.

Dietary phosphorus intake and increased serum phosphate levels are important stimuli to FGF-23 production, resulting in increased phosphaturia and reduced production of 1,25-dihydroxyvitamin D. In patients with CKD, phosphate excretion decreases with progressive declines in glomerular filtration rate.

However, serum phosphorus levels are often maintained in the normal range, in part due to increased production of FGF-23. The hormone increases phosphate excretion in the urine and reduces phosphate intestinal absorption by reducing 1,25-dihydroxyvitamin D levels.

Data suggest that the compensatory increases in FGF-23 may be harmful. Elevated levels of FGF-23 were found to be an independent predictor of CKD progression (J Am Soc Nephrol. 2007;18:2600-2608). More concerning are data indicating that elevated C-terminal and intact FGF-23 levels are associated with increased mortality in patients starting hemodialysis (N Engl J Med. 2008;359:584-592).

Control of hyperphosphatemia is essential. Perhaps targeting FGF-23 with phosphate binders will better influence the effects on bone histology, but the negative effects of FGF-23 will also have to be addressed.

Drs. Khosla and Sprague are affiliated with Northwestern University Feinberg School of Medicine. Dr. Khosla is Assistant Professor of Medicine and Dr. Sprague is Professor of Medicine. In addition, Dr. Khosla is an Attending Nephrologist and Dr. Sprague is Chief of Nephrology and Hypertension at North Shore University Health System in Evanston, Ill.
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