Phosphate binders for preventing and treating bone disease in chronic kidney disease patients

People with chronic kidney disease (CKD) develop impaired excretion of the dietary phosphorus. This results in a condition known as mineral and bone disorder in chronic kidney disease (CKD-MBD). CKD-MBD is characterized by high bone turnover, increased musculoskeletal morbidity including bone pain and muscle weakness, and vascular calcification which may contribute to the high incidence of cardiovascular disease and associated deaths. Several agents such as phosphate binders, vitamin D compounds, and calcimimetics are widely used to slow the development and progression of CKD-MBD complications.

Several phosphate binders, including aluminium and calcium-containing agents, have been widely used since 1970. The use of newer non-calcium or aluminium-based agents, such as sevelamer hydrochloride compounds and lanthanum carbonate is increasing although the cost is greater than the older phosphate binders. The avoidance of calcium-based binding agents to lower phosphorus in CKD theoretically reduces the risk of vascular calcification and cardiovascular disease. The balance between calcium-free phosphate binders reducing clinical events in CKD versus their cost remains controversial. Recently released KDIGO guidelines recommend restricting the use of calcium-based binders in people with persistent or recurrent hypercalcaemia or arterial calcification, or both.

We identified 60 studies, enrolling 7631 participants comparing phosphate binders to placebo or other phosphate binders. There was no significant reduction in all-cause mortality (10 studies, 3079 participants) or serum calcium by phosphorus product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in phosphorus (16 studies, 3126 participants) and parathyroid hormone (12 studies, 2551 participants) levels, but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants) with calcium salts compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride compared to calcium salts (5 studies, 498 participants). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants) and the calcium by phosphorous product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies.

Available phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing phosphate binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.

Authors' conclusions: 

Available phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing phosphate binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.

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Background: 

Phosphate binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact in CKD remains controversial.

Objectives: 

To review the effects of various phosphate binders on biochemical and patient-level end-points in CKD stages 3 to 5D.

Search strategy: 

In March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group's Specialised Register and CENTRAL for relevant studies.

Selection criteria: 

Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various phosphate binders in adults with CKD.

Data collection and analysis: 

Two authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model.

Main results: 

Sixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in serum phosphorus (16 studies, 3126 participants: MD 0.23 mg/dL, 95% CI 0.04 to 0.42) and parathyroid hormone (PTH) (12 studies, 2551 participants; MD 56 pg/mL, 95% CI 26 to 84) but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants: RR 0.45, 95% CI 0.35 to 0.59) with calcium-based agents compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride in comparison to calcium salts (5 studies, 498 participants: RR 1.58, 95% CI 1.11 to 2.25). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants: MD -0.30 mg/dL, 95% CI -0.64 to -0.25) and the Ca x P product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies.

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