Calcitriol in the Management of Secondary Hyperparathyroidism of Renal Failure Racquel E. Daisley-Kydd, Pharm.D., and Nancy A. Mason, Pharm.D. Secondary hyperparathyroidism (HPT) is characterized by persistent hypersecretion of parathyroid hormone (PTH), and produces characteristics of hyperparathyroid bone disease and a variety of biochemical and hormonal derangements. Management of uremic secondary HPT involves both prevention and treatment. Among preventive measures are attempts to control serum phosphate and serum calcium concentrations through dietary restriction, administration of phosphate binders, and calcium supplementation. Treatment with a vitamin D analog such as calcitriol returns plasma calcium concentrations toward normal and suppresses PTH secretion. The availability of a parenteral formulation of calcitriol, and new information regarding alternative routes of administration and regimens employing oral pulse dosing have renewed interest in calcitriol for the management of uremic secondary HPT. (Pharmacotherapy 1996;16(4):6 19-630) OUTLINE disease, including osteitis fibrosa and Pathophysiology of Secondary HPT osteosclerosis, and a variety of biochemical and Clinical Manifestations hormone derangements that may in turn cause Diagnosis the dysfunction of other organ systems.24 Management The medical management of this disorder is Calcitriol multimodal and creates a constant challenge to New Vitamin D Analogs the health care team. Practitioners are continually Summary searching for new and innovative approaches to slow the progression of bone disease and Hyperparathyroidism (HPT) is defined as the improve patients’ quality of life. A recent excess or inappropriate secretion of parathyroid advance in this area is the use of newer dosing hormone (PTH) associated with hyperplasia of strategies for parenteral calcitriol. the parathyroid glands. Secondary HPT associated with chronic renal failure results from Pathophysiology of Secondary HPT long-standing chronic hypocalcemic stimulation and partial end organ resistance to the metabolic The pathogenesis of secondary HPT is actions of PTH.l This condition occurs almost complex. Hypocalcemia, the recognized universally in patients with chronic renal failure stimulus for the synthesis and secretion of PTH, in whom persistent hypersecretion of PTH can is the product of several factors, including produce characteristics of hyperparathyroid bone phosphate retention, decreased production of active vitamin D (1,25-(OH)zD3) secondary to From Clinical Safety Surveillance, Procter & Gamble decreased renal mass and hyperphosphatemia, Pharmaceuticals, Cincinnati, Ohio (Dr. Daisley-Kydd); and reduced gastrointestinal absorption of calcium the College of Pharmacy, University of Michigan, and the due to both decreased production of active Department of Pharmacy, University of Michigan Medical vitamin D and depressed calcium transport in the Center, Ann Arbor, Michigan (Dr. Mason). Address reprint requests to Nancy A. Mason, Pharm.D., uremic state, and peripheral resistance to the College of Pharmacy, University of Michigan, 428 Church actions of PTH.’”, Street, Ann Arbor, MI 48109-1065. To understand the disturbances in mineral 620 PHARMACOTHERAPY Volume 16, Number 4, 1996 homeostasis, primarily calcium and phosphate, mechanism.6, in patients with chronic renal failure, it is The kidneys lose a substantial portion of their necessary to appreciate the interrelationships ability to produce 1,25-(OH)2D3in patients with between PTH and 1,25-(OH)zD3, the control uremia and reduced functional renal mass mechanisms involved in their synthesis and (Figure 2). This results in a decline in the secretion, and their modes of action (Figure 1). intestinal absorption of calcium and eventual In humans, the chief regulators of calcium hypocalcemia. Hypocalcemia is further homeostasis are PTH and 1,25-(OH)zD3. perpetuated by hyperphosphatemia, a direct Parathyroid hormone is the principal hormone consequence of decreased phosphate clearance.' involved in the routine regulation of ionized Decreased clearance ind subsequent calcium levels in the extracellular fluid, with accumulation of biologically active as well as 1,25-(OH)2D3 playing a key role in maintaining inactive PTH fragments in the circulation also calcium balance. The two also exercise occur in renal impairment. Reduced clearance of regulatory effects on each other. For example, other hormones such as catecholamines may PTH stimulates the production of 1 ,25-(OH)2D3 contribute to excessive PTH secretion in by activating the renal a-hydroxylase enzyme. secondary HPT through their ability to promote Active vitamin D suppresses the synthesis and PTH production by an unknown mechani~m.~? release of PTH by inhibiting PTH gene In addition, the mechanisms that normally transcription through interaction with specific suppress PTH release are impaired. In receptor proteins in target cells that have high individuals with normal renal function, a high affinity and specificity for 1,25-(OH)2D3.6,' serum calcium concentration acts as a trigger to Active vitamin D enters the circulation and is suppress PTH synthesis and s,ecretion. In uremic transported by the vitamin D-binding protein to patients with hyperplastic parathyroid glands, the target tissues where it interacts with native concentration of calcium necessary to suppress receptors. The net result is that it augments the PTH secretion is higher (so-called shift in set intestinal absorption of calcium and phosphorus point) since the parathyroids are relatively from the diet. High levels of serum calcium in insensitive to negative feedback control^.^ turn suppress PTH secretion by a feedback Reduced availability of 1,25-(OH)zD3 and a Negahve Feedback ............................Negahve Feedback + - - - _ - - - - I -> ' -1 \L Renal phosphate reabsorphon 1' Renal calnum reabsorphon I __-__ I I I -1 Figure 1. Parathyroid hormone axis regulation. CALCITRIOL FOR SECONDARY HYPERPARATHYROIDISM Daisley-Kydd and Mason 621 shift in calcium set point are the leading causes the treatment of this condition. of impaired suppression of PTH secretion. Conditions outside of the PTH axis can also Therefore, adequate suppression of PTH contribute to the development or exacerbation of secretion may require high and potentially toxic HPT in renal failure. Accumulation of aluminum serum calcium levels. lo Peripheral resistance to can impair bone mineralization and contribute to the effects of PTH and the persistent stimulus of the heterogeneity of the osteodystrophy that hypocalcemia leads to redirection of PTH activity occurs in renal failure.l2 Traditionally, the most to bone, causing the integrity of bone to be common source of aluminum intake in patients sacrificed in an effort to maintain normal levels receiving dialysis was aluminum-containing of calcium. phosphate binders, however, these are no longer The role of phosphate retention in the recommended as first-line treatment of hyper- pathogenesis of secondary HPT was the subject phosphatemia. Thus, aluminum bone disease is of recent study Phosphate accumulation in renal much more rare now than in the past.5 Metabolic failure is known to contribute to HPT indirectly acidosis has also been correlated with secondary by causing hypocalcemia through 1,25-(OH)lD3 HPT, and it has been suggested that correcting suppression and the reciprocal relationship with pH could help reduce PTH 1e~els.l~ serum calcium concentrations. Reversal of hyperphosphatemia by dietary restriction, Clinical Manifestations phosphate binders, and dialysis can therefore Clinical manifestations of secondary HPT in help correct hypocalcemia. Further evidence renal disease vary depending on disease severity. from a study in rats suggests that dietary Patients with renal failure typically have phosphate restriction may suppress PTH hypocalcemia and hyperphosphatemia. Bone secretion through a mechanism independent of pain, muscle weakness, pruritus, and skeletal 1,25-(0H)lD3 or serum calcium concentrations." abnormalities (renal osteodystrophy) are This reinforces the importance of dietary phos- common.12 The skeletal abnormalities include phate restriction and phosphate management in osteomalacia, generalized osteopenia, osteo- J Toxicity Mcrabolic acidosis Figure 2. Pathophysiology and treatment of secondary hyperparathyroidism associated- with renal failure. 622 PHARMACOTHERAPY Volume 16, Number 4, 1996 sclerosis, and osteitis fibrosa cystica (increased renal failure requires both prevention and osteoclastic resorption of the calcified bone with treatment. The initial preventive focus is replacement by fibrous tissue). Skeletal directed at maintaining serum calcium and pathology may reflect osteitis due to the phosphate levels within the normal range. In the excessive production of PTH in the initial stages face of fulminant disease, treatment requires of renal impairment. In later stages, effects of the reducing parathyroid mass and healing the bone impaired formation of 1,25-(OH)2D3 become disease and other complications.’ If these more evident and osteomalacia predominates. measures fail to achieve a desirable outcome, Generalized osteopenia and subsequent patho- parathyroidectomy is the definitive treatment. logic fractures could also occur, particularly in However, the availability of Ealcitriol is important patients undergoing long-term hem~dialysis.~,l2 in reducing the need for parathyroidectomy in The most significant extraskeletal ramification these patient^.'^ of persistently elevated