Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting. Alterations in the control mechanisms for calcium and phosphorus homeostasis occur early in the course of CKD and progress as kidney function decreases; if left untreated, then alterations can result in significant consequences. The disorders of bone have to be considered not only with regard to the bone itself but also with regard to the consequences of disturbed mineral metabolism at extraskeletal sites, including the vasculature. In recognition of the broad spectrum of disorders of mineral metabolism in this clinical setting, it has been recommended that terms such as “renal osteodystrophy” and “renal bone disease” give way to the term “CKD-mineral and bone disorder” to describe this broad clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD that can be manifested by any one or a combination of the following: (1) Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), and vitamin D metabolism; (2) abnormalities of bone turnover, mineralization, volume, linear growth, and strength; and (3) vascular or soft tissue calcification (1).
The abnormalities in bone in the setting of CKD include the effects of high levels of PTH on bone, which results in the high-turnover bone disease osteitis fibrosa. In addition, in the setting of CKD, a different skeletal abnormality known as adynamic bone, which is characterized by an extremely low bone turnover, may occur. Some cases may demonstrate mineralization defects and show frank osteomalacia. This wide spectrum of skeletal abnormality can give rise to a variety of mixed patterns, with elements of the effects of hyperparathyroidism on bone together with mineralization defects, and is known as mixed renal osteodystrophy. In addition, other systemic processes that may affect the skeleton, such as the accumulation of β-2 microglobulin or the systemic effects of postmenopausal osteoporosis or steroid-induced osteoporosis, may complicate the picture. A wide variety of disturbances of bone metabolism may occur in the setting of CKD. An understanding of the pathogenesis of these abnormalities then becomes essential to design a rational approach to their treatment and to the prevention of complications.
Pathogenesis of Metabolic Bone Disease in CKD
High-Turnover Metabolic Bone Disease in CKD
High-turnover bone disease is the result of the development of secondary hyperparathyroidism. It has been known for many years that hyperplasia of the parathyroid glands and high levels of PTH in blood occur early in the course of CKD (2,3). Numerous factors that lead to the overactivity of parathyroid glands in this clinical setting have been uncovered (Figure 1). These factors include the retention of phosphorus, decreases in the levels of calcitriol, intrinsic alterations within the parathyroid gland that give rise to increased PTH secretion as well as increased parathyroid growth, skeletal resistance to the actions of PTH, and hypocalcemia. Although each of the abnormalities is considered separately here, it is important to emphasize that these all are closely interrelated and one or more of these factors may predominate at different times throughout the course of kidney disease and likely will vary according to the particular type and the rapidity of progression of CKD.
Role of Phosphate Retention.
The major role of phosphate retention in the pathogenesis of secondary hyperparathyroidism has been demonstrated by a series of studies over many years (4–7). The original proposal was that phosphate retention, as a result of reductions in GFR, would cause transient decreases in the levels of ionized calcium, which would, in turn, trigger an increase in PTH secretion and a new steady state would be achieved, with restoration of normal calcium and phosphate levels but with the consequence that high levels of PTH now would be required to maintain homeostasis. The “tradeoff” for the maintenance of normal concentrations of calcium and phosphorus was the development of hyperparathyroidism (8). Substantial support for the proposal was produced by several studies. It was clearly shown that a high phosphate diet results in parathyroid hyperplasia (9,10). More important, perhaps, was the demonstration that reductions of dietary phosphorus, in proportion to the degree of a reduction in GFR, was successful in preventing the development of hyperparathyroidism, and these observations were confirmed subsequently in clinical studies (11). Although it is beyond question that phosphate retention plays a role in the pathogenesis of hyperparathyroidism, the mechanism by which it mediates this effect is not well defined, and many potential mechanisms need to be considered.
In normal humans, it has been shown that an oral phosphorus load results in an increase in serum phosphorus, a decline in the level of ionized calcium, and an increase in the levels of PTH in blood. However, there is doubt whether this occurs in early kidney failure, because hyperphosphatemia is not seen, even in patients whose PTH is already elevated (12,13). Similarly, hypocalcemia is not common in many patients with CKD, and there has been difficulty in demonstrating intermittent hypocalcemia after phosphate loading (12,14). Therefore, there is considerable doubt that this is the mechanism that accounts for the phosphate-induced effects on parathyroid function. In fact, experimental studies in which hypocalcemia was prevented by feeding a high-calcium diet, hypocalcemia did not occur and, in fact, increased slightly, even though hyperparathyroidism occurred (15). It is clear that hypocalcemia is not an essential factor for the development of hyperparathyroidism in the setting of CKD, and other factors must be involved.
It has been demonstrated that the production of calcitriol is regulated by phosphorus, such that phosphorus retention could lead to a decrease in the levels of calcitriol in blood (16). It has been shown in the experimental setting that administration of calcitriol in amounts that are sufficient to prevent a fall in the levels of calcitriol in blood is successful in preventing the development of hyperparathyroidism (15). This mechanism also potentially could explain the effects of phosphate restriction in ameliorating hyperparathyroidism, because a low-phosphate diet might augment the production of calcitriol.
Because studies in experimental animals have shown that phosphate seems to affect parathyroid function independent of calcium or calcitriol, it is likely that phosphate mediates these effects directly. This possibility was demonstrated by two groups of investigators, who independently demonstrated that changes in extracellular phosphorus concentrations in vitro resulted in an increased secretion of PTH in the absence of changes in ionized calcium (17–19). The mechanism by which phosphorus affects PTH secretion is not well understood at the present time. It has been shown, however, that the effects of high phosphorus concentrations to increase PTH secretion is a posttranscriptional effect, and these observations have led to studies of the effect of phosphorus on the stability of PTH mRNA (20). It has been demonstrated that the stability of PTH mRNA seems to be regulated by phosphorus, and this effect seems to be mediated by proteins (e.g., Au-rich RNA binding factor 1 [AUF1]) within the parathyroid gland that bind to the 3′ untranslated region of the PTH gene transcript (21–23). Additional investigations have demonstrated that high extracellular phosphate concentrations reduce the production of arachidonic acid by parathyroid tissue, an effect that is associated with an increase in PTH secretion (24). It is possible that this signaling mechanism may be the result of changes in cytosolic calcium on the phospholipase A2–arachidonic acid pathway. It is not known, however, how high phosphorus levels could affect the regulation of intracellular calcium in parathyroid cells.
Phosphorus also seems to have major effects on parathyroid growth. In animals that are on a high-phosphorus diet, there is an acceleration of parathyroid growth, whereas a low-phosphorus diet prevents parathyroid hyperplasia (25,26). Studies in experimental animals have shown that this effect of dietary phosphorus on parathyroid growth occurs extremely rapidly, within days after the induction of kidney failure (27) (Figure 2). This observation may have important implications for therapy.
The effect of a low-phosphorus diet to prevent parathyroid growth seems to be mediated by an increase in the cell-cycle regulator p21 (28). There seems to be a different pathway for phosphate-stimulated parathyroid growth, and studies have shown that TGF-α expression increases in the parathyroid gland, and similar increases of TGF-α by high-phosphorus diet in uremic animals have been demonstrated (28–30). Increased concentration of TGF-α in the parathyroid gland could interact with the EGF receptor and lead to activation of the mitogen-activated protein kinase and the induction of cyclin-1 to drive the cell into a proliferation cycle. The mechanism by which phosphorus mediates these effects is not understood at the present time, and although a type III phosphate transporter seems to exist in parathyroid glands, there is no evidence that this transporter mediates the effects of phosphorus on PTH secretion (31).
Role of Decreased Synthesis of Calcitriol.
Because the principal site for the production of calcitriol is the kidney, it is no surprise that decreases in kidney mass lead to a decrease in the ability of the kidneys to produce calcitriol. In the course of CKD, the decreased production of calcitriol contributes to the development of secondary hyperparathyroidism. Calcitriol levels seem to decline slowly and progressively throughout the course of CKD (14). These observations are somewhat surprising in that the increased levels of PTH would be expected to increase the activity of the 1-α-hydroxylase in the kidney in an effort to maintain these concentrations close to normal. That this does not occur is supported by studies that show a failure of the ability of PTH to increment calcitriol levels in patients with mild CKD (32). These observations indicate that other factors are involved in limiting the ability of the diseased kidney to increase calcitriol production. One such factor might be phosphate retention, because this can inhibit 1-α-hydroxylase (33). An additional factor may be fibroblast growth factor 23, which accumulates in renal failure and has been shown to decrease the production of calcitriol (34). Fibroblast growth factor 23 seems to be regulated by dietary phosphorus intake and the levels of serum phosphorus; therefore, this mechanism might play a role, at least in part, in the maintenance of phosphate homeostasis by regulating renal phosphorus excretion and also in mediating the effects of phosphorus on hyperparathyroidism (35).
In recent years, an additional mechanism that likely plays an extremely important role has been uncovered (36). It is known that 25-hydroxyvitamin D, the principle storage form of vitamin D, circulates bound to vitamin D–binding protein. This protein can be filtered at the glomerulus and enters the proximal tubular cell by a receptor-mediated mechanism that involves megalin, which is required for the uptake of 25-hydroxy–bound vitamin D–binding protein into the cell and facilitates the delivery of the precursor, 25-hydroxyvitamin D, to the 1-α-hydroxylase (36). In the course of CKD, decreased GFR results in decreased delivery of substrate to the 1-hydroxylase, which will limit the ability of the kidney to produce the active sterol. In addition, in human CKD, many patients have significant proteinuria, which will lead to the loss of vitamin D–binding protein with its bound ligand in the urine and contribute to the high incidence of vitamin D deficiency, manifested by low levels of 25-hydroxyvitamin D, in this clinical setting (37). Substrate limitation could impair the ability of the diseased kidney to increase calcitriol production.
As kidney disease advances, there are other factors that can limit the actions of calcitriol. This could occur because of decreases in the vitamin D receptor in target tissues (38–41) or from failure of the liganded vitamin D receptor to interact in a normal manner with its response element on DNA (42,43). Decreased vitamin D receptors have been demonstrated in the parathyroid glands of both humans and animals with kidney failure. In addition, it has been shown that ultrafiltrates of uremic plasma interfere with the interaction of the vitamin D receptor with DNA in vitro; therefore, there may be uremic toxins that can interfere with the normal actions of vitamin D.
Role of Intrinsic Alterations in the Parathyroid Gland.
Hypocalcemia is a powerful stimulus for PTH secretion and for parathyroid growth. The effects of calcium seem to be mediated by the calcium-sensing receptor, and several studies have demonstrated that there is decreased expression of the calcium-sensing receptor in the hyperplastic glands that are seen in kidney failure (44,45). The decrease in calcium-sensing receptors potentially could lead to increased PTH secretion because the response of the parathyroid glands to stimulation by calcium may be diminished. However, the relationship between the expression of the calcium-sensing receptor and the baseline levels of PTH is not clear. In a murine model of renal transplantation, PTH levels return to normal within a short time after transplantation, even though reduced calcium-sensing receptors still are present in the parathyroid gland (46). Studies in vitro also have dissociated the normalization of PTH levels from calcium-sensing receptor expression (47). Conversely, evidence also exists that the calcium-sensing receptor may play a role in parathyroid growth in that studies with calcimimetic agents in experimental animals have shown that activation of the calcium-sensing receptor by these means is associated with the prevention of parathyroid hyperplasia (48–50).
Decreased levels of calcitriol also may contribute to parathyroid abnormalities. Calcitriol is major regulator of PTH secretion, and the vitamin D receptor is expressed in the parathyroid glands. Calcitriol decreases PTH secretion in vivo and in vitro as a result of an effect at the level of transcription of the PTH gene (51,52). Calcitriol also may alter PTH secretion by other mechanisms. In addition to the indirect effects of increasing serum calcium by increasing intestinal calcium absorption, the direct effects of calcitriol may include increases in parathyroid vitamin D receptor, regulation of parathyroid growth, alteration in the expression of the calcium-sensing receptor, and possibly an effect on the set point for calcium-regulated PTH secretion. It has been demonstrated that vitamin D receptor expression is decreased in hyperplastic parathyroid glands that are seen in kidney disease (39,41), and it has been shown experimentally that administration of calcitriol is associated with upregulation of the vitamin D receptor and the calcium-sensing receptor in the parathyroid gland (53,54). An effect of calcitriol on parathyroid growth also has been demonstrated (55). This effect seems to involve the induction of the cyclin-dependent kinase inhibitor p21 (56). The role of calcitriol in parathyroid growth has been confirmed in vitamin D receptor knockout mice in which normalization of serum calcium corrects PTH levels but does not correct parathyroid hyperplasia (57).
The consequences of parathyroid growth also are important in the disordered parathyroid function of secondary hyperparathyroidism in kidney failure. It has been known for a long time that some parathyroid glands that have been resected at parathyroidectomy demonstrate numerous nodules and that staining for the vitamin D and calcium-sensing receptors is decreased markedly in these nodules (44,45). Some of these nodules may represent monoclonal expansions of parathyroid cells (58). An important question is whether the decreased expression of the calcium-sensing receptor and vitamin D receptor leads to the accelerated parathyroid growth or the accelerated growth somehow is associated with a reduction in the expression of these receptors. Studies by Ritter et al. (59) have demonstrated that parathyroid cell proliferation seems to precede the loss of the calcium-sensing receptor in parathyroid glands from animals with kidney failure.
Skeletal Resistance to the Actions of PTH.
A reduced calcemic response to the administration of PTH has been known for many years, and it also has been recognized that there is delayed recovery from induced hypocalcemia in patients with kidney disease (60,61). This phenomenon, known as skeletal resistance to the calcemic actions of PTH, may contribute to the development of hyperparathyroidism. Many factors likely are involved in this skeletal resistance, including phosphorus retention (62), possibly decreased levels of calcitriol (63–65), downregulation of the PTH receptor (66,67), and the potential actions of PTH fragments that have been shown to blunt the calcemic effect of PTH (68). Experimental support has been obtained for all of these factors.
Low-Turnover Metabolic Bone Disease in CKD
Low-turnover bone disease commonly is observed in patients with kidney disease, especially in patients who are on dialysis, and is characterized by an extremely slow rate of bone formation. Some cases demonstrate osteomalacia, which is characterized by defective bone mineralization in addition to the very slow bone formation rate. The osteomalacic lesion is due mostly to aluminum accumulation and is less common nowadays with decreased use of aluminum-based phosphorus binders (69). The adynamic bone of kidney disease is being found with increasing frequency (70) and has been described in some cases even before dialysis (71,72). The pathogenesis of adynamic bone is not well defined, but it seems that a number of factors might be involved (Figure 3) (73).
A number of these factors contribute to a relative state of hypoparathyroidism such as the administration of high calcium loads from calcium-containing phosphate binders or the use of high-dialysate calcium concentrations, as well as the use of potent vitamin D sterols. Age also may be a factor because many elderly patients may have low bone turnover on the basis of postmenopausal osteoporosis or osteopenia in association with systemic disease. Several other complications of the uremic state can lead directly lead to decreases in bone formation and include increases in the circulating concentrations of peptides that may decrease bone formation, such as osteoprotegerin and N-terminally truncated PTH fragments, undefined uremic toxins, acidosis, decreased expression of PTH receptors, alterations in concentrations of growth factors and cytokines that affect bone turnover, previous corticosteroid therapy–induced osteoporosis, or general malnutrition. One interesting growth factor is bone morphogenic protein-7, which initially was shown to have a beneficial effect in osteitis fibrosa (74) but was suggested recently to have a beneficial effect in adynamic bone (75).
Low-turnover osteomalacia in the setting of CKD has been recognized for many years. It now is clear that most cases of osteomalacia are associated with aluminum accumulation in bone, and its incidence has decreased markedly with the decreased use of aluminum-containing phosphorus binders.
Clinical Signs and Symptoms of Metabolic Bone Disease in CKD
Metabolic bone disease in patients with kidney disease often is asymptomatic, and symptoms appear only late in its course. Many of the symptoms are nonspecific and include pain and stiffness in joints, spontaneous tendon rupture, predisposition to fracture, and proximal muscle weakness. A similar set of symptoms may be seen in both the low- and high-turnover type of skeletal abnormality. It is important to emphasize that the absence of clinical signs and symptoms of metabolic bone disease do not underscore the importance of these abnormalities, because many of the processes that contribute to the underlying metabolic bone disease also have consequences at extraskeletal sites, and the control of these processes is important to decrease morbidity and mortality.
Extraskeletal calcifications, particularly involving the vasculature, and calcification of the skin and calciphylaxis also may be seen. Cardiovascular calcification is extremely common and important in patients with kidney disease, in whom it develops and progresses rapidly and predicts a variety of adverse outcomes. The various types of metabolic bone disease and associated mineral disorders may contribute to this. The processes that are responsible for vascular calcification are the focus of recent research (76,77). The evidence now suggests that vascular calcification is an active, regulated process that has many similarities to the process of skeletal mineralization. Studies suggest that the normal vessel wall expresses proteins that inhibit calcification such as matrix Gla protein. In addition, circulating proteins such as fetuin-A are produced at remote sites and act to inhibit soft tissue calcification systemically. However, alterations of these proteins may lead to a seeming transformation of vascular smooth muscle cells into osteo/chondrocytic-like cells that then facilitate calcification. Both clinical and basic research findings indicate an inverse relationship between bone mineralization and vascular calcification. The mechanisms that link these two processes are a topic of active investigation. A detailed discussion of extraskeletal calcification is beyond the scope of this review.
Biochemical Assessment of Metabolic Bone Disease in CKD
Although histologic examination of un-decalcified sections of bone remains the gold standard for the precise diagnosis of renal bone disease, bone biopsy is not widely used in clinical practice because of the invasive nature of the technique. Accordingly, a biochemical assessment of disorders of bone and mineral metabolism is the mainstay of the diagnosis and treatment. In addition to the measurements of calcium and phosphorus concentrations, which in their own right can contribute to hyperparathyroidism, it is essential to obtain a direct index of parathyroid activity by measurements of PTH. Measurements of calcium and phosphorus need to be obtained frequently, and therapy needs to be adjusted according to widely accepted clinical practice guidelines to maintain the calcium and phosphorus concentrations within defined ranges (78). Accurate assessment of PTH assays remains problematic, even though the assays for PTH have undergone substantial evolution in the past few decades (79). The early confusion over the interpretation of PTH assays after their initial introduction gave way to a more stable period with the introduction of two site immunometric assays, which were believed to measure intact PTH. It is on the basis of these first-generation immunometric assays that current therapeutic guidelines were provided. Further research in recent years, however, has complicated the interpretation of these results in that it is now known that these assays also measure, to varying degrees, N-terminally truncated PTH fragments in addition to intact PTH (80,81). It now seems that some biologic activities can be attributed to these N-terminally truncated PTH fragments, such as PTH 7-84, that seem to be opposite in direction to the actions of PTH on bone (68,82,83). This continues to be an active area of research. Further developments in PTH assay technique have introduced assays that now are more specific for the intact PTH (1-84) molecule (84). These assays have been instrumental in uncovering the potential biologic actions of the N-terminally truncated PTH fragments, such as PTH (7-84). Much needs to be learned about the biology and the effects of such PTH fragments before clinical applications and clinical decision making using these measurements or ratios between PTH 1-84 and PTH fragments such as 7-84 can be defined. These second-generation, more specific assays for PTH (1-84) are not widely available, and, accordingly, there is much more reliance on “intact PTH” assays of the first-generation type, which seem to perform well in clinical practice. However, although individual assays perform well, there is considerable variation in the results that are obtained with assays from different manufacturers, mainly because of the extent of cross-reactivity with the circulating N-terminally truncated PTH fragments (79,85). This issue complicates practice guidelines such that it seems inappropriate to require rigid adherence to the recommended PTH targets, because the various assays in use may give quantitatively different results. Efforts are under way, spearheaded by the National Kidney Foundation, to try to provide biologic standards that clinicians and investigators may use to help in the interpretation of PTH results.
A number of biologic markers of bone formation and bone resorption might be used in conjunction with measurement of the mineral ions and PTH to gauge hone cell activity. Of these, it seems that alkaline phosphatase and bone-specific alkaline phosphatase are most useful in this regard, and other proteins, such as osteocalcin, procollagen, propeptides, collagen breakdown products, tartrate-resistant acid phosphatase, and collagen C-terminal telopeptide, do not add clinical value, and much further work needs to be done to try to obtain useful biochemical assessments of bone cell activity.
Prevention and Management of Metabolic Bone Disease in CKD
The objectives for the management of metabolic bone disease in patients with CKD are to maintain the blood levels of calcium and phosphorus as close to normal as possible and to undertake measures to prevent the development or to begin the treatment of established hyperparathyroidism and to prevent the development of parathyroid hyperplasia. An additional goal is to prevent extraskeletal calcifications and to avoid oversuppression of bone turnover to the extent that adynamic bone might be induced. It also is necessary to avoid the accumulation of substances that may be toxic to bone, such as aluminum.
Central to the prevention and management of metabolic bone disease in this clinical setting is the ability to intervene early in the course of CKD, when this process begins, using a “stepped care” approach as illustrated in Figure 4. Disturbances in the regulation of calcium and phosphate homeostasis need to be evaluated by measurements of PTH when GFR is reduced. If PTH is elevated, then vitamin D status should be evaluated and treated if necessary. Recent data have raised another consideration in that kidney disease now is established to be a significant risk factor for vitamin D deficiency, and levels of 25-hydroxy vitamin D, the principal storage form of vitamin D and the best index of vitamin D nutrition, are found to be extremely low in a large majority of patients with CKD (37). Current recommendations are to correct this deficiency by administration of a vitamin D preparation such as ergocalciferol in sufficient dosage to raise 25-hydroxyvitamin D levels above 30 ng/ml. The clinical efficacy of this remains to be demonstrated with regard to the prevention of hyperparathyroidism. Dietary restriction of phosphorus may be used in early CKD to control the developing hyperparathyroidism, although protein restriction should be modest to avoid malnutrition. Other measures that have been shown to be successful include calcium supplementation, the use of phosphate binders and the use of vitamin D sterols such as calcitriol (86), the vitamin D prohormones alfacalcidol (87) and doxercalciferol (88), and the vitamin D analog paricalcitol (89). Practice guidelines also suggest that limitations of the amount of calcium-based phosphate binders also be considered (78), because some data suggest that large calcium loads may contribute to the progression of vascular calcifications in patients who have ESRD and are on hemodialysis. The introduction of non–calcium-containing phosphate binders can facilitate limiting calcium intake, and sevelamer hydrochloride has been extremely useful in patients who are on dialysis to help control serum phosphorus while simultaneously limiting calcium intake to the recommended values (90). Sevelamer has been shown to be associated with decreased progression of vascular calcifications (91). The recently introduced lanthanum carbonate also has been shown to be an effective phosphate binder that also can facilitate phosphorus control while limiting calcium intake (90).
In advanced kidney disease, the use of active vitamin D sterols can be useful in the control of hyperparathyroidism, and several preparations now are available in this regard. The native hormone calcitriol is available orally and intravenously and is effective but has a reasonably narrow therapeutic window between efficacy and toxicity. Other vitamin D sterols have been introduced, such as the vitamin D prohormones 1-α-hydroxyvitamin D3 and 1-α-hydroxyvitamin D2. Both of these sterols undergo 25-hydroxylation in the liver and become 1-25-dihydroxyvitamin D3 and 1-25-dihydroxy vitamin D2, respectively. Whereas in the therapeutic ranges, there is little difference between the ability of these vitamin D2 and vitamin D3 prohormones to raise calcium or phosphorus, there seems to be lesser toxicity associated with the vitamin D2 sterol when administered at high dosages, an effect that likely is due to alternative metabolic pathways (92,93).
An additional approach has been the introduction of vitamin D analogs, in which structural alterations in the vitamin D molecule have been introduced, to try to achieve some selectivity for suppression of PTH while minimizing the effects on calcium and phosphorus. Three such analogs have been introduced: 19-nor-1,25-dihydroxyvitamin D2 (94), 22-oxacalcitriol (95), and 26,27-hexafluorocalcitriol (96). 19-Nor-1,25-dihydroxyvitamin D2 is widely used in the United States and has been effective with somewhat lesser toxicity than the native sterol calcitriol (97). This was used initially in intravenous form in patients who were on hemodialysis but now is available in oral form and is being used in CKD stages 3 and 4, where it seems to be extremely effective with little toxicity (89). Although in experimental animals there are significant differences in the properties of various vitamin D analogs in terms of effects on calcium and phosphorus absorption as well as on vascular calcification (98–100), there are no comparative studies of the vitamin D analogs with regard to safety and efficacy in patients.
In recent years, there has been the intriguing observation that seems to suggest that administration of vitamin D sterols to patients who are on hemodialysis may be associated with a survival benefit compared with that of patients who do not receive any vitamin D sterol (101). The mechanism of such an effect is not known but raises the consideration that nonclassical effects of vitamin D may be playing a role. Similarly, a retrospective study of outcomes of patients who were treated with calcitriol compared with those who received paricalcitol demonstrated that there seemed to be a survival benefit to receiving the vitamin D analog paricalcitol (102). Again, the mechanism of such an effect is not known and clearly requires further detailed study.
The calcimimetic cinacalcet provides another therapeutic agent for the control of hyperparathyroidism in patients with ESRD and has been shown to be effective in reducing the levels of PTH (103,104). This agent, which is an allosteric activator of the calcium-sensing receptor, results in a lowering of serum calcium and can facilitate keeping the concentration of serum calcium within the recommended targets. Cinacalcet therapy also results in a small decrease in phosphorus concentrations in patients with ESRD that also is favorable to meeting the practice guidelines. This approach is especially useful for patients who have serum calcium and phosphorus at or slightly above the upper limits of normal and in whom the use of vitamin D sterols might be problematic. Calcimimetic therapy can be used in combination with any and all of the approaches discussed.
As a result of detailed investigations in the past 4 decades, there have been considerable advances in the understanding of the pathophysiology of the many patterns of metabolic bone disease that occur in CKD. These observations have led to a rational approach to therapy and to the discovery and introduction of new therapeutic agents that may be used to modify this complication of kidney disease. These approaches also have continued to lead to the uncovering of new areas of interest that continue to require investigation, such as the efforts to understand and to modify vascular calcification, to understand the biologic significance of N-terminally truncated PTH fragments, and to understand the biologic significance of the nonclassical effects of the vitamin D system. It is hoped that, as a result of these advances, the outcomes of the patients with CKD can be improved.
Published online ahead of print. Publication date available at www.jasn.org.
1. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G: Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69 : 1945 –1953, 2006
2. Reiss E, Canterbury JM, Kanter A: Circulating parathyroid hormone concentration in chronic renal insufficiency. Arch Intern Med 124 : 417 –422, 1969
3. Arnaud CD: Hyperparathyroidism and renal failure. Kidney Int 4 : 89 –95, 1973
4. Slatopolsky E, Caglar S, Pennell JP, Taggart DD, Canterbury JM, Reiss E, Bricker NS: On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50 : 492 –499, 1971
5. Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS: On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney Int 2 : 147 –151, 1972
6. Slatopolsky E, Bricker NS: The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 4 : 141 –145, 1973
7. Slatopolsky E, Delmez JA: Pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 23 : 229 –236, 1994
8. Bricker NS: On the pathogenesis of the uremic state. An exposition of the “trade-off hypothesis.” N Engl J Med 286 : 1093 –1099, 1972
9. Laflamme GH, Jowsey J: Bone and soft tissue changes with oral phosphate supplements. J Clin Invest 51 : 2834 –2840, 1972
10. Jowsey J, Reiss E, Canterbury JM: Long-term effects of high phosphate intake on parathyroid hormone levels and bone metabolism. Acta Orthop Scand 45 : 801 –808, 1974
11. Rutherford WE, Bordier P, Marie P, Hruska K, Harter H, Greenwalt A, Blondin J, Haddad J, Bricker N, Slatopolsky E: Phosphate control and 25-hydroxycholecalciferol administration in preventing experimental renal osteodystrophy in the dog. J Clin Invest 60 : 332 –341, 1977
12. Portale AA, Booth BE, Halloran BP, Morris RCJ: Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73 : 1580 –1589, 1984
13. Wilson L, Felsenfeld A, Drezner MK, Llach F: Altered divalent ion metabolism in early renal failure: Role of 1,25(OH)2D. Kidney Int 27 : 565 –573, 1985
14. Martinez I, Saracho R, Montenegro J, Llach F: The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 29 : 496 –502, 1997
15. Lopez-Hilker S, Galceran T, Chan YL, Rapp N, Martin KJ, Slatopolsky E: Hypocalcemia may not be essential for the development of secondary hyperparathyroidism in chronic renal failure. J Clin Invest 78 : 1097 –1102, 1986
16. Tanaka Y, Deluca HF: The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 154 : 566 –574, 1973
17. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, Dusso A, MacDonald PN, Brown AJ: Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97 : 2534 –2540, 1996
18. Almaden Y, Hernandez A, Torregrosa V, Canalejo A, Sabate L, Fernandez Cruz L, Campistol JM, Torres A, Rodriguez M: High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 9 : 1845 –1852, 1998
19. Almaden Y, Canalejo A, Hernandez A, Ballesteros E, Garcia-Navarro S, Torres A, Rodriguez M: Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 11 : 970 –976, 1996
20. Kilav R, Silver J, Naveh-Many T: Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest 96 : 327 –333, 1995
21. Yalcindag C, Silver J, Naveh-Many T: Mechanism of increased parathyroid hormone mRNA in experimental uremia: Roles of protein RNA binding and RNA degradation. J Am Soc Nephrol 10 : 2562 –2568, 1999
22. Sela-Brown A, Naveh-Many T, Silver J: Transcriptional and post-transcriptional regulation of PTH gene expression by vitamin D, calcium and phosphate. Miner Electrolyte Metab 25 : 342 –344, 1999
23. Sela-Brown A, Silver J, Brewer G, Naveh-Many T: Identification of AUF1 as a parathyroid hormone mRNA 3′-untranslated region-binding protein that determines parathyroid hormone mRNA stability. J Biol Chem 275 : 7424 –7429, 2000
24. Almaden Y, Canalejo A, Ballesteros E, Anon G, Rodriguez M: Effect of high extracellular phosphate concentration on arachidonic acid production by parathyroid tissue in vitro. J Am Soc Nephrol 11 : 1712 –1718, 2000
25. Naveh-Many T, Rahamimov R, Livni N, Silver J: Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest 96 : 1786 –1793, 1995
26. Yi H, Fukagawa M, Yamato H, Kumagai M, Watanabe T, Kurokawa K: Prevention of enhanced parathyroid hormone secretion, synthesis and hyperplasia by mild dietary phosphorus restriction in early chronic renal failure in rats: Possible direct role of phosphorus. Nephron 70 : 242 –248, 1995
27. Denda M, Finch J, Slatopolsky E: Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure. Am J Kidney Dis 28 : 596 –602, 1996
28. Dusso AS, Pavlopoulos T, Naumovich L, Lu Y, Finch J, Brown AJ, Morrissey J, Slatopolsky E: p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int 59 : 855 –865, 2001
29. Dusso AS, Sato T, Arcidiacono MV, Alvarez-Hernandez D, Yang J, Gonzalez-Suarez I, Tominaga Y, Slatopolsky E: Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl 102 : S8 –S11, 2006
30. Cozzolino M, Lu Y, Sato T, Yang J, Suarez IG, Brancaccio D, Slatopolsky E, Dusso AS: A critical role for enhanced TGF-alpha and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease. Am J Physiol Renal Physiol 289 : F1096 –F1102, 2005
31. Tatsumi S, Segawa H, Morita K, Haga H, Kouda T, Yamamoto H, Inoue Y, Nii T, Katai K, Taketani Y, Miyamoto KI, Takeda E: Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. Endocrinology 139 : 1692 –1699, 1998
32. Ritz E, Seidel A, Ramisch H, Szabo A, Bouillon R: Attenuated rise of 1,25 (OH)2 vitamin D3 in response to parathyroid hormone in patients with incipient renal failure. Nephron 57 : 314 –318, 1991
33. Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA: Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146 : 5358 –5364, 2005
34. Fukagawa M, Kazama JJ: With or without the kidney: The role of FGF23 in CKD. Nephrol Dial Transplant 20 : 1295 –1298, 2005
35. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M: Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16 : 2205 –2215, 2005
36. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96 : 507 –515, 1999
37. Gonzalez EA, Sachdeva A, Oliver DA, Martin KJ: Vitamin D insufficiency and deficiency in chronic kidney disease. A single center observational study. Am J Nephrol 24 : 503 –510, 2004
38. Merke J, Hugel U, Zlotkowski A, Szabo A, Bommer J, Mall G, Ritz E: Diminished parathyroid 1,25(OH)2D3 receptors in experimental uremia. Kidney Int 32 : 350 –353, 1987
39. Korkor AB: Reduced binding of [3H]1,25-dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure. N Engl J Med 316 : 1573 –1577, 1987
40. Brown AJ, Dusso A, Lopez-Hilker S, Lewis-Finch J, Grooms P, Slatopolsky E: 1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int 35 : 19 –23, 1989
41. Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y: Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92 : 1436 –1443, 1993
42. Patel SR, Ke HQ, Vanholder R, Koenig RJ, Hsu CH: Inhibition of calcitriol receptor binding to vitamin D response elements by uremic toxins. J Clin Invest 96 : 50 –59, 1995
43. Sawaya BP, Koszewski NJ, Qi Q, Langub MC, Monier-Faugere MC, Malluche HH: Secondary hyperparathyroidism and vitamin D receptor binding to vitamin D response elements in rats with incipient renal failure. J Am Soc Nephrol 8 : 271 –278, 1997
44. Gogusev J, Duchambon P, Hory B, Giovannini M, Goureau Y, Sarfati E, Drueke TB: Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 51 : 328 –336, 1997
45. Kifor O, Moore FD Jr, Wang P, Goldstein M, Vassilev P, Kifor I, Hebert SC, Brown EM: Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 81 : 1598 –1606, 1996
46. Lewin E, Garfia B, Recio FL, Rodriguez M, Olgaard K: Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation. J Am Soc Nephrol 13 : 2110 –2116, 2002
47. Ritter CS, Martin DR, Lu Y, Slatopolsky E, Brown AJ: Reversal of secondary hyperparathyroidism by phosphate restriction restores parathyroid calcium-sensing receptor expression and function. J Bone Miner Res 17 : 2206 –2213, 2002
48. Mizobuchi M, Hatamura I, Ogata H, Saji F, Uda S, Shiizaki K, Sakaguchi T, Negi S, Kinugasa E, Koshikawa S, Akizawa T: Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency. J Am Soc Nephrol 15 : 2579 –2587, 2004
49. Wada M, Nagano N, Furuya Y, Chin J, Nemeth EF, Fox J: Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism. Kidney Int 57 : 50 –58, 2000
50. Wada M, Furuya Y, Sakiyama J, Kobayashi N, Miyata S, Ishii H, Nagano N: The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest 100 : 2977 –2983, 1997
51. Silver J, Russell J, Sherwood LM: Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A 82 : 4270 –4273, 1985
52. Russell J, Lettieri D, Sherwood LM: Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 119 : 2864 –2866, 1986
53. Brown AJ, Zhong M, Finch J, Ritter C, McCracken R, Morrissey J, Slatopolsky E: Rat calcium-sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol 270 : F454 –F460, 1996
54. Naveh-Many T, Marx R, Keshet E, Pike JW, Silver J: Regulation of 1,25-dihydroxyvitamin D3 receptor gene expression by 1,25-dihydroxyvitamin D3 in the parathyroid in vivo. J Clin Invest 86 : 1968 –1975, 1990
55. Kremer R, Bolivar I, Goltzman D, Hendy GN: Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto-oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology 125 : 935 –941, 1989
56. Cozzolino M, Lu Y, Finch J, Slatopolsky E, Dusso AS: p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium. Kidney Int 60 : 2109 –2117, 2001
57. Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN, Goltzman D: Inactivation of the 25-hydroxyvitamin D-1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 279 : 16754 –16766, 2004
58. Arnold A, Brown MF, Urena P, Gaz RD, Sarfati E, Drueke TB: Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 95 : 2047 –2053, 1995
59. Ritter CS, Finch JL, Slatopolsky EA, Brown AJ: Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor. Kidney Int 60 : 1737 –1744, 2001
60. Evanson JM: The response to the infusion of parathyroid extract in hypocalcaemic states. Clin Sci 31 : 63 –75, 1966
61. Massry SG, Coburn JW, Lee DB, Jowsey J, Kleeman CR: Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects. Ann Intern Med 78 : 357 –364, 1973
62. Somerville PJ, Kaye M: Evidence that resistance to the calcemic action of parathyroid hormone in rats with acute uremia is caused by phosphate retention. Kidney Int 16 : 552 –560, 1979
63. Somerville PJ, Kaye M: Resistance to parathyroid hormone in renal failure: Role of vitamin D metabolites. Kidney Int 14 : 245 –254, 1978
64. Massry SG, Stein R, Garty J, Arieff AI, Coburn JW, Norman AW, Friedler RM: Skeletal resistance to the calcemic action of parathyroid hormone in uremia: Role of 1,25 (OH)2 D3. Kidney Int 9 : 467 –474, 1976
65. Galceran T, Martin KJ, Morrissey JJ, Slatopolsky E: Role of 1,25-dihydroxyvitamin D on the skeletal resistance to parathyroid hormone. Kidney Int 32 : 801 –807, 1987
66. Olgaard K, Arbelaez M, Schwartz J, Klahr S, Slatopolsky E: Abnormal skeletal response to parathyroid hormone in dogs with chronic uremia. Calcif Tissue Int 34 : 403 –407, 1982
67. Picton ML, Moore PR, Mawer EB, Houghton D, Freemont AJ, Hutchison AJ, Gokal R, Hoyland JA: Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure. Kidney Int 58 : 1440 –1449, 2000
68. Slatopolsky E, Finch J, Clay P, Martin D, Sicard G, Singer G, Gao P, Cantor T, Dusso A: A novel mechanism for skeletal resistance in uremia. Kidney Int 58 : 753 –761, 2000
69. Gonzalez E, Martin K: Aluminum and renal osteodystrophy: A diminishing clinical problem. Trends Endocrinol Metab 3 : 371 –375, 1992
70. Malluche HH, Mawad H, Monier-Faugere MC: The importance of bone health in end-stage renal disease: out of the frying pan, into the fire? Nephrol Dial Transplant 19[Suppl 1] : i9 –i13, 2004
71. Torres A, Lorenzo V, Hernandez D, Rodriguez JC, Concepcion MT, Rodriguez AP, Hernandez A, de Bonis E, Darias E, Gonzalez-Posada JM, et al.: Bone disease in predialysis, hemodialysis, and CAPD patients: Evidence of a better bone response to PTH. Kidney Int 47 : 1434 –1442, 1995
72. Hernandez D, Concepcion MT, Lorenzo V, Martinez ME, Rodriguez A, De Bonis E, Gonzalez-Posada JM, Felsenfeld AJ, Rodriguez M, Torres A: Adynamic bone disease with negative aluminium staining in predialysis patients: Prevalence and evolution after maintenance dialysis. Nephrol Dial Transplant 9 : 517 –523, 1994
73. Couttenye MM, D’Haese PC, Verschoren WJ, Behets GJ, Schrooten I, De Broe ME: Low bone turnover in patients with renal failure. Kidney Int 56 : S70 –S76, 1999
74. Gonzalez EA, Lund RJ, Martin KJ, McCartney JE, Tondravi MM, Sampath TK, Hruska KA: Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7. Kidney Int 61 : 1322 –1331, 2002
75. Lund RJ, Davies MR, Brown AJ, Hruska KA: Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model. J Am Soc Nephrol 15 : 359 –369, 2004
76. Shanahan CM: Mechanisms of vascular calcification in renal disease. Clin Nephrol 63 : 146 –157, 2005
77. Moe SM: Vascular calcification and renal osteodystrophy relationship in chronic kidney disease. Eur J Clin Invest 36[Suppl 2] : 51 –62, 2006
78. Eknoyan G, Levin A, Levin NW: Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42 : 1 –201, 2003
79. Martin KJ, Akhtar I, Gonzalez EA: Parathyroid hormone: New assays, new receptors. Semin Nephrol 24 : 3 –9, 2004
80. Brossard JH, Cloutier M, Roy L, Lepage R, Gascon-Barre M, D’Amour P: Accumulation of a non-(1-84) molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure: Importance in the interpretation of PTH values. J Clin Endocrinol Metab 81 : 3923 –3929, 1996
81. D’Amour P, Brossard JH, Rousseau L, Nguyen-Yamamoto L, Nassif E, Lazure C, Gauthier D, Lavigne JR, Zahradnik RJ: Structure of non-(1-84) PTH fragments secreted by parathyroid glands in primary and secondary hyperparathyroidism. Kidney Int 68 : 998 –1007, 2005
82. Nguyen-Yamamoto L, Rousseau L, Brossard JH, Lepage R, D’Amour P: Synthetic carboxyl-terminal fragments of parathyroid hormone (pth) decrease ionized calcium concentration in rats by acting on a receptor different from the pth/pth-related peptide receptor. Endocrinology 142 : 1386 –1392, 2001
83. Langub MC, Monier-Faugere MC, Wang G, Williams JP, Koszewski NJ, Malluche HH: Administration of PTH-(7-84) antagonizes the effects of PTH-(1-84) on bone in rats with moderate renal failure. Endocrinology 144 : 1135 –1138, 2003
84. Gao P, Scheibel S, D’Amour P, John MR, Rao SD, Schmidt-Gayk H, Cantor TL: Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1-84: Implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res 16 : 605 –614, 2001
85. Souberbielle JC, Boutten A, Carlier MC, Chevenne D, Coumaros G, Lawson-Body E, Massart C, Monge M, Myara J, Parent X, Plouvier E, Houillier P: Inter-method variability in PTH measurement: Implication for the care of CKD patients. Kidney Int 70 : 345 –350, 2006
86. Ritz E, Kuster S, Schmidt-Gayk H, Stein G, Scholz C, Kraatz G, Heidland A: Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial). Nephrol Dial Transplant 10 : 2228 –2234, 1995
87. Brandi L, Nielsen PK, Bro S, Daugaard H, Olgaard K: Long-term effects of intermittent oral alphacalcidol, calcium carbonate and low-calcium dialysis (1.25 mmol L-1) on secondary hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis. J Intern Med 244 : 121 –131, 1998
88. Coburn JW, Maung HM, Elangovan L, Germain MJ, Lindberg JS, Sprague SM, Williams ME, Bishop CW: Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 43 : 877 –890, 2004
89. Coyne D, Acharya M, Qiu P, Abboud H, Batlle D, Rosansky S, Fadem S, Levine B, Williams L, Andress DL, Sprague SM: Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis 47 : 263 –276, 2006
90. Chertow GM, Burke SK, Dillon MA, Slatopolsky E: Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 15 : 559 –276, 2000
91. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62 : 245 –252, 2002
92. Sjoden G, Smith C, Lindgren U, DeLuca HF: 1alpha-Hydroxyvitamin D2 is less toxic than 1alpha-hydroxyvitamin D3 in the rat. Proc Soc Exp Biol Med 178 : 432 –436, 1985
93. Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HL, Bishop CW, Knutson JC: Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-Hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum. J Clin Endocrinol Metab 83 : 2156 –2166, 1998
94. Martin KJ, Gonzalez EA, Gellens M, Hamm LL, Abboud H, Lindberg J: 19-Nor-1-alpha-25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact PTH in patients on hemodialysis. J Am Soc Nephrol 9 : 1427 –1432, 1998
95. Tsukamoto Y, Hanaoka M, Matsuo T, Saruta T, Nomura M, Takahashi Y: Effect of 22-oxacalcitriol on bone histology of hemodialyzed patients with severe secondary hyperparathyroidism. Am J Kidney Dis 35 : 458 –464, 2000
96. Akiba T, Marumo F, Owada A, Kurihara S, Inoue A, Chida Y, Ando R, Shinoda T, Ishida Y, Ohashi Y: Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 32 : 238 –246, 1998
97. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D: Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 63 : 1483 –1490, 2003
98. Finch JL, Brown AJ, Slatopolsky E: Differential effects of 19-nor-1,25-(OH)2 D2 on calcium and phosphate resorption in bone [Abstract]. J Am Soc Nephrol 8 : 573A –1490, 1997
99. Finch JL, Brown AJ, Slatopolsky E: Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone. J Am Soc Nephrol 10 : 980 –985, 1999
100. Hirata M, Katsumata K, Endo K, Fukushima N, Ohkawa H, Fukagawa M: In subtotally nephrectomized rats 22-oxacalcitriol suppresses parathyroid hormone with less risk of cardiovascular calcification or deterioration of residual renal function than 1,25(OH)(2) vitamin D(3). Nephrol Dial Transplant 18 : 1770 –1776, 2003
101. Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA Jr, Thadhani R: Activated injectable vitamin D and hemodialysis survival: A historical cohort study. J Am Soc Nephrol 16 : 1115 –1125, 2005
102. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R: Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349 : 446 –456, 2003
103. Moe SM, Cunningham J, Bommer J, Adler S, Rosansky SJ, Urena-Torres P, Albizem MB, Guo MD, Zani VJ, Goodman WG, Sprague SM: Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant 20 : 2186 –2193, 2005
104. Goodman WG: Calcimimetic agents for the treatment of secondary hyperparathyroidism. Semin Nephrol 24 : 460 –463, 2004