Continuing Education - Massachusetts College of Pharmacy and Health Sciences

Therapies for Secondary Hyperparathyroidism back to menu

Phosphate Binders

As mentioned earlier, there is a complex balancing act between PTH, calcium, phosphorous, and vitamin D. As PTH rises, it liberates more calcium and phosphorous from bones. The resulting high phosphorous in turn further stimulates PTH release. Unfortunately, with the reduced ability of the kidneys to eliminate the excess phosphorous, PTH and phosphorous both continue to rise and the risk of soft tissue calciphylaxis increases. Dietary restriction of phosphate (<1 g/day) is recommended in the early stages of CKD despite normal serum levels. For patients with phosphate levels exceeding 4.6 mg/dL, dietary restriction should be continued with the addition of oral phosphate binder therapy which, when administered with a meal, will reduce dietary phosphate absorption in the gut.⁵

For many years, aluminum salts were the binders of choice, because they created a nonabsorbable aluminum phosphate precipitate in the intestinal lumen. Unfortunately, therapeutic doses occasionally resulted in aluminum intoxication side effects: vitamin D-resistant osteomalacia, myopathy, dementia, and refractory microcytic anemia.⁷

Despite a better safety profile, calcium salts bind dietary phosphorus less effectively than aluminum salts (ie, aluminum hydroxide).⁸ Although calcium binders are generally less effective than aluminum, numerous studies have shown that calcium binders alone are, in fact, able to normalize phosphate concentrations in a high percentage of dialysis patients; for this reason, calcium binders have become the most commonly utilized therapy.

Calcium-based phosphate binders can be effective in lowering serum phosphorus levels and may be used as the initial or primary binder therapy in non-dialysis patients.⁵ However, the use of calcium binders in high doses to control serum phosphorus in CKD patients can result in positive calcium balance. The issue of positive calcium balance and its potential to increase the risk of cardiac complications is a topic of recent debate at the national level.^9-12 NKF recommends that the total dose of elemental calcium from phosphate binders not exceed 1.5 g/day.⁵ The NKF guidelines further recommend avoiding calcium phosphate binders in dialysis patients when serum calcium levels exceed 10.2 mg/dL, when iPTH levels are 150 pg/mL or less, or when the calcium-phosphorous product is greater than 55. Lastly, the guidelines advocate avoiding calcium in patients with existing soft-tissue calcification.⁵

Recent research into the potential cardiovascular risks associated with calcium-containing phosphate binders has promoted growing interest in the use of non-calcium containing agents. Sevelamer hydrochloride was considered the first agent to be free of potentially toxic metals. Studies have shown that sevelamer effectively controls serum phosphate in hemodialysis patients without developing hypercalcemia.^{13, 14} In addition, the drug has had an unanticipated beneficial effect on binding bile salts and reducing LDL cholesterol.^15-17 While sevelamer is FDA-approved for use in hemodialysis patients, data on its utilization in stages 3 and 4 CKD is lacking.

The FDA recently approved the second non-calcium/non-aluminum binder for ESKD patients, lanthanum carbonate. Unlike sevelamer, lanthanum is available as a chewable product. Studies have shown that lanthanum accumulates in human bone.¹⁸ Due to limited experience with the use of lanthanum, it is unknown if the accumulation in human tissue or organs poses any harmful long-term effects. Additionally, like sevelamer, published studies of lanthanum use in stages 3 and 4 CKD are unavailable.

Choice of agent depends on calcium levels and/or risk for hypercalcemia. Whatever the choice, most patients are required to take multiple tablets with each meal or snack. Regular education reinforcement may be necessary to insure proper adherence to the regimen and prevent unnecessary side effects or dose escalation. Whether stomach pH influences drug activity has been questioned on multiple occasions; however, since phosphorous is primarily absorbed in the small intestine, clinical relevance has not been established.¹⁹

Vitamin D Hormone Therapy

Vitamin D hormones are produced and secreted by healthy kidneys under tight regulation by parathyroid hormone (PTH). Research on these hormones began with a narrow focus on bone disease; however, the research focus has expanded substantially with discoveries that vitamin D hormones have roles in many other organ functions and disease processes that are independent of calcium homeostasis, including hypertension, cardiac dysfunction, Type I diabetes, prostate cancer, immune system dysfunction, erythroid dysfunction, and muscular dystrophy.²⁰

Inadequate renal production of 1,25-dihydroxyvitamin D occurs as early as Stage 2 CKD, possibly resulting from a simple nutritional deficiency of vitamin D (from which the vitamin D hormones are produced), but more likely due to the declining ability of the kidneys to make and secrete the hormones.⁵ The K/DOQI guidelines recommend that if the iPTH is above the target range for the given stage of CKD, serum 1,25-dihydroxyvitamin D should be measured. If the level is less than 30 ng/mL, treatment with ergocalciferol (1,000 to 2,000 IU/day) should begin. Therapy with an active Vitamin D hormone should replace ergocalciferol if the iPTH remains above the target range and the serum 1,25-dihydroxyvitamin D level is greater than 30 ng/mL. Future K/DOQI guidelines may drop the current recommendation to begin therapy with ergocalciferol before moving directly to hormone replacement therapy.

At present, there are 3 vitamin D hormone replacement therapies available in the United States: calcitriol, doxercalciferol, and paricalcitol. Since all 3 products have proven efficacy in reducing iPTH, selection of a particular therapy is based on other considerations, including the risks for drug-induced hypercalcemia and hyperphosphatemia. The primary comparison is made based on the hypercalcemia risk. Oral therapies are normally employed in CKD Stages 3 and 4, but are often used in Stage 5 for patients undergoing peritoneal dialysis. Intravenous therapy is almost exclusively used in ESKD patients on hemodialysis. While oral therapy can be used for hemodialysis patients, Medicare reimbursement and improved patient adherence result in a greater utilization of the intravenous formulation in that subpopulation. At present, oral calcitriol, oral doxercalciferol and oral paricalcitol are approved for use in CKD Stages 3 and 4; however, the lack of clinical studies for oral paricalcitol (ie, all available data are derived from the intravenous formulation) has led some third party payers to exclude it from their formularies.²⁰ Table 2 shows current guidelines for initiating treatment, and recommended initial doses. Dose titration can be compared to warfarin therapy. While some clinicians prefer to titrate the daily dose, “pulse therapy” of higher doses on certain days of the week has also proven beneficial.^21-23

Calcimimetic Therapy

Calcimimetic agents engage calcium receptors in the parathyroid, stimulating the feedback mechanism that results in reduced PTH production. Cinacalcet is the only agent currently available in this class and it is indicated only for ESKD patients. Placebo-controlled studies found that cinacalcet lowered serum iPTH by 26% to 43% and decreased the calcium-phosphorus product by 8% to 15% in ESKD patients.^24-27 Despite these outcomes, cinacalcet remains a third-line therapy because it does not directly address vitamin D deficiency and phosphate excess, which impact various other organs and tissues. Furthermore, cinacalcet has been studied in conjunction with active vitamin D hormones and may produce outcomes from a synergistic mechanism. In contrast to other therapies available, cinacalcet has a risk of hypocalcemia, and does not currently have a role in the management of patients with CKD stages 3 and 4.^26-27

Formulary Choices and Costs

Medicare has a special carve-out payment for injectable vitamin D hormones in patients with ESKD on hemodialysis. Therefore, Table 3 focuses on a cost comparison of available oral agents that may be utilized in CKD Stages 3 and 4.

The consequences of hyperparathyroidism and hyperphosphatemia vary. With the increasing concerns about soft tissue calcification and cardiovascular risks, interest has developed for using non-calcium phosphate binders, vitamin D hormones with a reduced risk of hypercalcemia, and calcimimetics. However, careful consideration must be given to coordinating the chosen therapies. Although the medication choices may be relatively few, determining the ideal combination can be multifarious, potentially changing in an individual patient as the disease progresses.

At present, one unanswered question about combining medications is whether the clinical advantage lies in combining a non-calcium phosphate binder with calcitriol, or combining a calcium-based phosphate binder with a lower-risk vitamin D hormone. In addition, although some have postulated that cinacalcet’s reduced risk of hypercalcemia may make it a mainstay therapy in CKD patients with cardiovascular disease, the more recently identified direct impact of vitamin D on vascular smooth muscle cell proliferation has reinforced the current recommendation that vitamin D hormones be utilized first, adding cinacalcet when needed for additive or synergistic activity to reduce iPTH.²⁸

To assist in the formulary decision process, some Pharmacy & Therapeutics committees have established clinical prior authorization criteria for the use of high cost agents. For example:

Sevelamer and lanthanum have been reserved for ESKD patients with hyperphosphatemia that is not controlled by calcium binders alone or those with hypercalcemia or an elevated calcium-phosphorus product, or documented calciphylaxis.
Cinacalcet has been limited to third-line therapy addition in ESKD patients who have not met their clinical goals and are not at risk for hypocalcemia.

The notable difference between these 2 drug class restrictions is that sevelamer or lanthanum will replace the other binder therapies, while cinacalcet is not meant to replace established therapy but to supplement it. In the end, access to all of the given therapies must be provided based on the needs of each patient as determined by clinically established guidelines.