Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease: An Overview

George R. Bailie, PharmD, PhD, FCCP; Shaul G. Massry, MD

Disclosures

Pharmacotherapy. 2005;25(12):1687-1707. 

In This Article

Guideline 5: Use of Phosphorus Binders in Chronic Kidney Disease

Guideline Statements

In Stages 3 and 4

5.1 - If phosphorus or iPTH concentrations cannot be controlled within the target range despite dietary phosphorus restriction, phosphorus binders should be prescribed (O).

5.2 - Calcium-based phosphorus binders are effective in lowering serum phosphorus concentrations (E) and may be used as the initial binder therapy (O).

In Stage 5

5.3 - Both calcium-based phosphorus binders and other non-calcium-, non-aluminum-, non-magnesium-containing phosphorus-binding agents (such as sevelamer hydrochloride) are effective in lowering serum phosphorus concentrations (E), and either may be used as the primary therapy (O).

5.4 - In patients undergoing dialysis who remain hyperphosphatemic (serum phosphorus concentration > 5.5 mg/dl [1.78 mmol/L]) despite the use of either calcium-based phosphorus binders or other non-calcium-, non-aluminum-, non-magnesium-containing phosphorus binders, a combination of both should be used (O).

5.5 - The total dosage of elemental calcium provided by the calcium-based phosphorus binders should not exceed 1500 mg/day (O), and the total intake of elemental calcium (including dietary calcium) should not exceed 2000 mg/day (O).

5.6 - Calcium-based phosphorus binders should not be used in patients undergoing dialysis who are hypercalcemic (corrected serum calcium concentration of > 10.2 mg/dl [2.54 mmol/L]) or whose plasma PTH concentrations are below 150 pg/ml (16.5 pmol/L) on two consecutive measurements (E).

5.7 - Non-calcium-containing phosphorus binders are preferred in patients undergoing dialysis who have severe vascular and/or other soft-tissue calcifications (O).

5.8 - In patients with serum phosphorus concentrations above 7.0 mg/dl (2.26 mmol/L), aluminum-based phosphorus binders may be used as a short-term therapy (4 wks) and for one course only, to be replaced thereafter by other phosphorus binders (O). In such patients, more frequent dialysis should also be considered (E).

This set of guidelines includes information that is critical to the appropriate choice and management of phosphorus binder therapy. Pharmacists may have a definitive role in this process, since in some instances a clear benefit exists to the selection of one class of phosphorus-binding agent over another. When dietary phosphorus restriction is inadequate to control the serum concentration of phosphorus and/or plasma concentration of PTH, the second line of therapy is the administration of phosphorus binders. Different compounds may be appropriate for different patient situations, and no one agent appears to be optimal for every clinical circumstance. Table 4 provides the characteristics of various phosphorus-binding agents, and Table 5 lists the calcium content of calcium-containing phosphorus binders.

The goal of phosphorus binder therapy is to maintain serum phosphorus concentrations within the target range without negatively affecting nutritional status or causing serious adverse effects. Thus, phosphorus binder therapy should be started when serum phosphorus concentrations are elevated despite patient compliance with dietary phosphorus restriction; or when serum phosphorus concentrations can be controlled by a dietary phosphorus restriction only, but when such dietary intervention hinders the intake of other critical nutrients; or when blood PTH concentrations remain elevated after dietary phosphorus restriction, even if the serum phosphorus concentrations are not elevated.

Choice of Phosphorus Binder

Note that throughout these guidelines, reference is made to non-calcium-, non-aluminum-, non-magnesium-containing phosphorus-binding agents. At the time the guidelines were written, sevelamer hydrochloride was the only phosphorus-binding agent of this type. One additional agent—lanthanum carbonate—was approved recently but is not yet commercially available. To our knowledge, no prospective, controlled studies have evaluated phosphorus binders in stages 3 and 4 CKD. A meta-analysis compared the efficacy of the phosphorus binders on outcomes, including serum concentrations of phosphorus and calcium, plasma concentration of PTH, bone biochemical markers, and extraskeletal calcification in stage 5 CKD.[3] No studies available at that time evaluated the effect of phosphorus binders on patient quality of life, mortality rate, frequency of bone disease or fractures, or bone histomorphometry by bone biopsy measurements. In every study, serum phosphorus concentration was lowered by the phosphorus binder studied. Calcium carbonate led to more hypercalcemic events compared with other phosphorus binders, but the available data do not provide guidance regarding the choice of the appropriate calcium-based phosphorus binder for controlling the calcium-phosphorus product. Sevelamer led to lower serum cholesterol concentrations compared with placebo or calcium acetate, primarily due to a decrease in low-density lipoprotein cholesterol concentrations. The evidence supports the hypothesis that all of the current phosphorus binders are effective in controlling serum phosphorus concentrations.

Patient compliance with prescribed binder therapy ranges from 30-100%.[11,22] None of the available data dealt with the effect of non-compliance on clinical outcomes. Although maintenance of high serum phosphorus concentrations could be due to noncompliance with phosphorus binders, other factors, such as dietary indiscretion and phosphorus release from the bone by severe hyperparathyroidism, also must be considered. Few studies have examined the optimal timing for ingestion of phosphorus binders, but opinion is that binders should be taken 10-15 minutes before, or during, a meal to maximize contact with ingested phosphorus.

In stages 3 and 4 CKD, calcium concentrations are often low, contributing to secondary hyper-parathyroidism. Furthermore, because these patients have some residual kidney function, phosphorus and/or PTH control is usually achievable with lower doses of calcium-based phosphorus binders. In stage 5 CKD, the choice of phosphorus binder should be determined by patient preference, compliance, comorbid illnesses, adverse effects, cost, and the ability to control serum phosphorus concentrations while maintaining the desired calcium-phosphorus product (< 55 mg2/dl2) and limiting the total calcium intake. Sevelamer (and, presumably, lanthanum) is recommended as the therapy of choice in patients undergoing dialysis who have low PTH concentrations. The rationale for this recommendation is that these patients will usually have low-turnover bone disease, and the bone will be unable to incorporate a calcium load, predisposing to extraskeletal calcification. Further, calcium-based phosphorus binders should not be used in patients with hypercalcemia or with vascular calcification. In these situations, a non-calcium-, non-magnesium-, non-aluminum-containing phosphorus binder should be used to control serum concentrations of phosphorus while avoiding excessive calcium intake. This aspect of treatment is the subject of considerable interest and debate.

Aluminum-Based Phosphorus Binders

Because of the risk of neurotoxicity, anemia, and osteomalacia, the routine use of aluminum-containing phosphorus binders has been abandoned. Such therapy may be reserved only for patients with serum phosphorus concentrations above 7.0 mg/dl (2.26 mmol/L) and only for short-term therapy (4 wks). This approach would quickly lower serum phosphorus concentrations. When this is achieved, aluminum-based compounds should be replaced by other phosphorus binders. Although long-term aluminum intake is associated with increased morbidity, increased mortality is associated with phosphorus concentrations above 6.5 mg/dl (2.10 mmol/L).[5] Thus, the two concerns must be balanced. Short-term use of aluminum-containing phosphorus binders does not appear to lead to development of aluminum bone disease or neurotoxicity. However, calcium citrate should be avoided while the patients receive aluminum-based compounds, since citrate increases the absorption of aluminum from the intestine and may precipitate acute aluminum toxicity.

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