UPDATE ON RENAL OSTEODYSTROPHY: PATHOGENESIS AND CLINICAL MANAGEMENT

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1 UPDATE ON RENAL OSTEODYSTROPHY: PATHOGENESIS AND CLINICAL MANAGEMENT KhashayarSakhaee,M.D. University of Texas Southwestern Medical Center at Dallas Internal Medicine Grand Rounds May 22, 1997

2 Name: Rank: Division: Areas of Interest: Khashayar Sakhaee, M.D. Professor Mineral Metabolism Disorders of mineral metabolism

3 INTRODUCTION Renal osteodystrophy is the term used to describe the skeletal complications of end-stage renal disease. It is a complex disorder involving an excess stimulation of PTH synthesis and secretion, a relative or absolute decrease in serum calcitriol, a decrease in serum calcium concentration and an increase in serum phosphorus concentration (1,2). Recently, the role of various cytokines such as interleukin-1, tumor necrosis factor a, interleukin-6, interleukin-11, and their receptors or circulating antagonists have been considered (3-6). These cytokines along with calcitropic hormones are involved in bone remodeling and their activity is increased in patients with end-stage renal disease (Fig. 1 ). Besides these factors, abnormal regulations of parathyroid gland cell growth and replication are involved (7,8). It is conceivable that as a result of these alterations, diffuse parathyroid hyperplasia progresses to hyperplasia with nodular transformations containing monoclonally growing cells and eventually to diffuse invasion of the entire gland by monoclonal parathyroid cells. Abnormal regulation of parathyroid gland cell growth J..J.. Ca ttp J.. Ca-Sensor Fig. 1. Pathogenesis of Renal Osteodystrophy The development of bone disease in patients with chronic renal failure has received much attention, especially since the introduction of dialysis which extended these patients life expectancy. Renal osteodystrophy is classified as high to low bone turnover states, according to the histologic features (Table 1 ). 1

4 Table 1. Classification of Renal Osteodystrophy Disorder Osteitis fibrosa Osteomalacia Adynamic renal bone disease Description Increased remodeling - resorption and formation Defective mineralization, increased osteoid No remodeling, hypocellular bone surface Pathogenesis Secondary hyperparathyroidism, role of cytokines and growth factors Aluminum deposition, plus unknown factors Increased suppressors of bone remodeling or deficiencies of growth factors, aluminum deposition, parathyroid hormone suppression The development of treatment regimens that can maintain normal serum calcium and phosphorus concentrations, reduce parathyroid hormone secretion, and normalize a deficiency of 1,25-dihydroxyvitamin D (1,25-(0HhD) have resulted in decreases in frequency and severity of osteitis fibrosa, the most common type of renal osteodystrophy. During the 1970's and 1980's, the spectrum of renal osteodystrophy was broadened. It was discovered that an accumulation of aluminum from water used for dialysis and aluminum salts used as phosphate binders caused osteomalacia and an adynamic bone disease. The recognition of these disorders led to changes in the composition of dialysis fluids and substitution of calcium salts for aluminum salts. Consequently, the frequency of aluminum-related bone disease is diminishing (9). However, adynamic bone disease, is being increasingly detected without the presence of aluminum deposition in bone. This lesion has been observed with increasing frequency in the elderly, diabetic patients, chronic ambulatory peritoneal dialysis (CAPO) patients, and patients on calcium salts as phosphate binders (9-17). Therefore, it entails the involvement of other factors, including the potential role of inhibitors of bone remodeling and the possible deficiency of bone growth factors. The heterogeneous nature of renal osteodystrophy may also be geographical in origin. The considerable variation in the dietary phosphorus intake, differences in climate and latitude accounting for effect on vitamin D production, and calcium and vitamin D intake depending on cultural circumstances, provide yet another possible factor. 2

5 PATHOGENESIS Secondary Hyperparathyroidism (High-Turnover Bone Disease) The association of severe chronic renal insufficiency, marked hyperplasia of parathyroid glands, and skeletal lesion was demonstrated in the 1930's (18). At that time parathyroid hyperplasia was thought to be a primary disturbance with metabolic bone disease, nephrocalcinosis, and renal failure consequences. Albright et al (19) first suggested that"... the kidney damage might be the cause and not the result of parathyroid tumors... ". In later years with the advent of radioimmunoassays (RIAs) for PTH measurement (20-22), high circulating levels of PTH have been detected at earlier stages of chronic renal failure (Fig. 2) and skeletal bone disease was characterized in bone biopsy of patients with mild to moderate chronic renal failure (23, 24 ) E c::r 240 -G) ::s X 160 I.... Q cln (ml/min/1. 73 m 2 ) Fig. 2. PTH vs Renal Clearance Of Inulin In Patients With Varying Levels Of Renal Function The pathogenetic importance of the above findings has led to considerable effort to define the main factors which are involved in development of parathyroid hyperplasia and/or secondary hyperparathyroidism. These factors include phosphorus (P) retention, hypocalcemia, and decreased serum 1,25-dihydroxyvitamin D (Fig. 3). The mechanisms by which these factors control PTH release are complex and interrelated. 3

6 + p.... Fig. 3. Pathogenesis of Secondary Hyperparathyroidism Phosphorus Retention The most attractive hypothesis has been suggested by Bricker et al. (25) in their formulation of the "trade-off' hypothesis. They have suggested that secondary hyperparathyroidism in advancing renal disease may occur, to a major extent, as an expression of the adaptation of the biologic control system governing the maintenance of external P balance. The hypothesis was based upon the assumption that each time a permanent fall in glomerular filtration rate (GFR) occurs in chronic renal disease, the absolute rate of phosphorus excretion must fall transiently; if phosphorus intake remains constant, there must follow a period of phosphorus retention in the body until the rate of phosphorus excretion by the residual nephrons is adjusted upwards. According to this hypothesis, the adaptation in phosphorus excretion occurs through the following mechanisms. With the transient rise in serum phosphorus, a reciprocal fall in ionized calcium of the blood occurs, and this leads to an increase in PTH secretion. The high level of PTH would reduce tubular reabsorption of phosphorus, cause phosphaturia, and return both serum phosphorus and calcium levels toward normal but at the expense of a higher circulating PTH level (Fig. 4). 4

7 GFR, mumfn 120 P, mg/100 ml \ 1\ 1\ 1\_ Ca, mg/100 ml v v v v- 60 PTH, units Fig. 4. Secondary Hyperparathyroidism in Advancing Chronic Renal Disease Considerable evidence supports an important role of phosphorus retention in the development of secondary hyperparathyroidism. In experimentally induced chronic renal failure (26) a reduction of dietary phosphorus intake in proportion to the decrease in GFR largely prevented the development of secondary hyperparathyroidism in dogs with chronic renal failure (Fig. 5). 5

8 :I 0 GFR, [] mllmln [D I ~I 0 [] P Intake, mg/24hr [D I P, mg/100ml Ca, mg/100 ml PTH, units :I D D D D :I D D D D ~I TRP,% ~1 D D D D Fig. 5. Secondary Hyperparathyroidism and Phosphorus Intake Several investigators have provided evidence for a role of phosphorus retention in pathogenesis of secondary hyperparathyroidism, but the mechanism of this effect remains unclear. In normal humans (27) and in patients with moderate renal insufficiency (28) restriction of dietary phosphorus increases the production rate of 1,25-dihydroxyvitamin D, which in tum decreases the level of immunoreactive PTH. However, this mechanism may not be involved in advanced renal insufficiency because the decrease in renal mass may limit the production of 1,25-dihydroxyvitamin D (29-31) (Table 2). 6

9 Table 2. Mechanics of Secondary PTH Stimulation in Chronic Renal Failure (CRF) Normals and Patients with Moderate CRF --+-.l. Serum P -+-I t 1 25-(0H).D t lntestln~l Ca.. J Patients with Advanced CRF --+-.l. Serum P - I-t 1,25-(0H).D 1-.l. =~~;a ~ I 8 - J.ea-._... '' It has been demonstrated, in dogs with advanced renal insufficiency (32) and severe secondary hyperparathyroidism, progressive reduction of dietary phosphorus was accompanied by a significant decrease in the levels of PTH without changes in ionized calcium or 1,25-dihydroxyvitamin D (Fig. 6). Thus, in severe chronic renal failure, phosphorus appears to regulate PTH secretion by a mechanism that is independent of 1,25-dihydroxyvitamin D. 5.5 Ionized Ca.., mg/dl Phosphorus, mg/dl 6 P<.02 8 P< P, 0,(, P,% ea.,% Ca..,% PTH, pg/ml Calcltriol, pg/ml o400 P< P<.05 P< P, 0,(, P, o,(, Ca... % Ca..,% Fig. 6. Effects of Dietary Phosphorus 7

10 The mechanism of the direct role of phosphorus on regulation of PTH synthesis and secretion is not yet known. Phosphorus may potentially affect the phospholipid composition of all membrane, calcium fluxes, vitamin D receptor (VDR), and perhaps, have an effect on the calcium sensor of parathyroid cell membrane. A very recent study has demonstrated that dietary phosphorus restriction not only prevents secondary hyperparathyroidism independent of serum ionized calcium and 1,25- (0HhD, but prevents parathyroid cell growth (33). Moreover, it has been shown for the first time a direct action of phosphorus in vitro to increase the rate of PTH synthesis (Fig. 7). The effect seems to be postranscriptional f 2! f uo 1100 'li 1.20 a l 0.10 cwoo!!i' 1:100 I~~ l ~ ~00 ~ i Ill: 100 ~~ 120 I 100 '! too Nonnal Umnlc l ~ 110 :100 ~ e 7 e,j.p tp,j.p tp Tlme,hn 20 Fig. 7. Effect of Phosphorus on Parathyroid Gland in Normal and Uremic Rats Altered Vitamin D Metabolism The kidney is the principal organ responsible for conversion of 25-hydroxyvitamin D (25-0HD) to 1,25-dihydroxyvitamin D (34,35). The nature of the response to replacement with various vitamin D metabolites supports that impaired conversion of 25-0HD to 1,25-(0H) 2 D plays a key role in the development of secondary hyperparathyroidism in patients with chronic renal failure (Fig. 8). It has been shown that intestinal 7 ca absorption at a normal level in uremic patients will be achieved by a significantly lower dose of 1,25-(0HhD than 25-0HD (36-38). 8

11 "C Cl) Q.30 0 en.25.q 25(0H)D 3 <.20 CIS (.),..15 c 0.10 I -, 1a(OH)D t;, 3.05 e u <l Dose J.LQ/day (log 10 scale) Fig.~- Vitamin D Effect in Advanced Renal Failure 1,25-dihydroxyvitamin D exerts a negative feedback control on parathyroid gland through direct and indirect mechanisms. It has been shown that in children and adults with moderate renal insufficiency (GFR of mllmin), serum 1,25-(0HhD is significantly reduced (39-42). A reduction in serum levels of 1,25-(0HhD could give rise to reduced intestinal calcium absorption. It has been demonstrated that fractional intestinal calcium absorption is decreased in a few patients with mild renal failure (43), over one half of patients with moderate renal failure, and in most of those with severe renal insufficiency. Decreased intestinal calcium absorption could result in a decrease in ionized blood. calcium concentration and thereby to an increased PTH release. The finding that the parathyroid gland contains specific intracellular receptors for 1,25-(0Hh D (44,45) has stimulated considerable attention to unravel the potential inhibitory role of 1,25-(0Hh D on PTH secretion, independent of its effect on serum calcium concentration. A direct inhibitory action of 1,25-dihydroxyvitamin D on mrna coding for Pre-Pro PTH (PTH-mRNA) in bovine parathyroid cell culture has been demonstrated (46-48). This reduction in PTH mrna occurs at the transcription level (Fig. 9). 9

12 Decreased Renal Mass Tubule PO/- Concentration t 1 a-hydroxylase Activity 4, Calcitriol Synthesis 4, PTH Gene Transcription t PTH Secretion t Fig. 9. Mechanism of Elevated PTH in Chronic Renal Failure Consequently, an increase in circulating 1,25-(0HhD suppresses the synthesis of PTH available for secretion, while a decrease in its circulating concentration stimulates PTH synthesis. The biological actions of 1,25-dihydroxyvitamin D proceeds through binding with specific vitamin D receptors (VDR) in target cells. A decrease in the number and affinity of calcitrol receptors in parathyroid tissue of uremic patients has been demonstrated (49-51 ). It is possible that reduced VDR number or function renders the parathyroid glands less responsive to the inhibitory action of 1,25-(0HhD (Fig. 1 0). 10

13 J. 1,25-(0H) 2 D Chronic Renal Failure ~ J. Intestinal Ca Absorption ~ J. Serum Ca.. t PTH.,,.,! + Phosphorus Retention J. Parathyroid 1,25-(0H) 2 D Receptors Fig Pathogenetic Mechanisms of Secondary Hyperparathyroidism in Chronic Renal Failure Role of Calcium Serum calcium is the major regulating factor of PTH synthesis and secretion. The direct and rapid stimulatory effect of low serum calcium on PTH secretion and rapid inhibitory effect of high serum calcium have been understood for many years. A decrease in serum calcium stimulates PTH secretion in 3 minutes by the parathyroid gland via the release of stored hormone from preformed secretory granules. Sustained stimulation by hypocalcemia is associated with changes in intracellular degradation of PTH, reutilization of degraded hormone, and mobilization of secondary pool (52). The fraction of intact PTH in the circulation varies inversely with serum calcium (53). Thus, the ratio of hormone fragments to intact hormone has been found to be 4-7 fold higher in the presence of hypercalcemia compared to hypocalcemia (54). During time periods from several hours in vitro to days or even weeks in vitro, a high extracellular calcium concentration reduces the expression of pre-pro PTH mrna, and low concentration stimulates PTH mrna expression (55-58). This more chronic effect of calcium probably is extended via a recently described negative calcium-responsive element of the human PTH gene (59). The mechanism by which the parathyroid cell detects and responds to changes in ionized calcium has recently been identified. It was demonstrated that changes in extracellular calcium concentration, other divalent cations and polycations elicited rapid changes in intracellular calcium concentration that were typical of responses activated by membrane-associated receptors (60-64 ). Such findings suggested the existence of a membrane-associated cation-sensing mechanism, possibly a receptor, in parathyroid cells. It was later demonstrated that a G-protein coupled, calcium sensing protein or calcium receptor was present in bovine parathyroid cells (60). 11

14 It has recently been shown that there is a substantial reduction in the immunoreactivity of the calcium-receptor protein in parathyroid adenoma as well as in parathyroid tumors from uremic subjects with severe secondary hyperparathyroidism (65,66). It is possible that this reduction in apparent receptor content plays a role in abnormal calcium-sensor regulated PTH release and, in turn, in the hypercalcemia observed in these patients (Fig. 11 ). 100 c fti 80 -en 0 c 00 :I E 60 o 0 o - 0 s 0 gg ~a ~ 0 en ~ c oo - Cl) 20 '=.5 :-:-- 0 Seconday Seconday Adenoma Adenoma HWorplasia Hyperplasia (Nonnal) Nonnal) Fig. 11. Uremic Hyperparathyroidism It remains to be determined whether pathogenesis of hyperparathyroidism represents a primary abnormality in cell growth with a secondary change in receptor expression, or primary reduction in receptor expression on predisposing to somatic mutation in genes controlling growth. Role of Cytokines It has recently been shown that expression of interleukin-1 (IL-1 ), tumor necrosis factor-a (TNF-a), interleukin- (IL-6) and interleukin-11 (IL-11) and their soluble receptors are increased in end-state renal disease, suggesting that they play a part in activation of remodeling in renal osteodystrophy (3-6). Parathyroid hormone, TNF-a and IL-1 stimulate production of osteoclasts at different stages of differentiation, leading to synergism when concentrations of cytokines and PTH are both elevated, as in chronic renal failure (66) (Fig. 12). These cytokines, PTH, TNF-a and IL-1, activate the resorptive process by stimulating the secretion of collagenase (67) and tissue plasminogen activator (68) and inhibiting the synthesis of collagen (69) and DNA (70). 12

15 Marrow Monocyte Preosteoclast IL-1,1;ye- + " TNF"t' \ Preosteoblast ~- StromaiCell _..... PTH /~ w,; treob,... ) i00 ~H Fig. 12. Activation of Bone Remodeling in Renal Osteodystrophy It has been demonstrated that therapy for end-stage renal disease activates the immune system and is responsible for the increased production of inflammatory cytokines (71,72). The enhanced release of these cytokines may be responsible for the musculoskeletal complications of end-stage renal disease, including muscular wasting, osteitis, adynamic bone disease, and beta-2-micro globulin (8 2 m) release and an amyloid bone disease. Role of the Abnormal Regulation of Parathyroid Gland Cell Growth The normal regulatory mechanisms involved in the control of normal parathyroid cell growth, division, and death have not yet been elucidated. However, the increase in parathyroid gland size in chronic renal disease has been well established (73). A calciumindependent PTH secretion (shift in "set point") parallels an increased parathyroid gland mass (74). Several factors may be involved independently or together in the pathogenesis of parathyroid cell growth in chronic renal failure (Fig. 13). Normal P...chyrold Gland (Polydonal Orowltl) ~(- JtiM-1) 0(,.._O(_eMoncing_ -0(--- c.----! IIDR "' lingle - (TGF-a?) Parathyroid Hyperplula +Nodule Fonnetion (Poly+ Morloc:lonll Growth) Fig. 13. Pathogenesis of Secondary and "Tertiary" Hyperparathyroidism in Chronic Renal Failure 13

16 The role of 1,25-dihydroxyvitamin D in renal osteodystrophy and its ability to prevent secondary hyperparathyroidism by increasing serum calcium concentration and inhibiting parathyroid hormone gene transcription (46) are well established. However, 1,25- dihydroxyvitamin D also inhibits cell proliferation by decreasing expression of c-myc protooncogenes, which regulate the cell cycle (75). In experimental uremic rats, physiological doses of 1,25-dihydroxyvitamin D given prophylactically early in the course of the uremia, prevented the stimulation of parathyroid cell proliferation (73). However, this inhibitory effect was attenuated when calcitriol was administered later during uremic state. The development of nodular parathyroid growth within hyperplastic tissue has been shown to increase in end-stage renal disease patients on chronic hemodialysis (76). The monoclonal growth within polyclonal hyperplastic glands may imply somatic mutation of a gene or genes controlling cell cycle regulation. The regulatory factors involved in the development of monoclonal nodular parathyroid cell growth in these patients have not been yet elucidated. The impaired capacity of DNA repair, a specific activation of tumor-enhancing genes (PRADI) or deletion of tumor-suppressor genes (RB tumor-suppressor genes) have been implicated-(77,78). An allelic deletion on chromosome 11 has recently been identified. This is believed to be responsible for under expression of tumor-suppressor genes in parathyroid glands in the dialysis patients (79). It is also possible that mutations involved in vitamin-d receptor genes and calciumsensing receptor genes (60) are involved. Vitamin-D receptor expression is decreased or absent in monoclonal nodule (51). It has also been shown that de-novo expression of transforming growth factor-a (TGF-a) mrna and protein is increased in parathyroid glands of patients on hemodialysis, in contrast to the lack of expression of TGF-a in normal parathyroid glands (80). A significant expression of epidermal growth factor receptor (EGF-R) has been detected which suggests that TGF-a by binding to EGF-R in an autocrine manner promotes proliferation of parathyroid cells. Osteomalacia (Low-Turnover Bone Disease) The prevalence of osteomalacia in patients with end-stage renal disease is decreasing (9, 15). Osteomalacia is characterized by low rates of bone turnover, a mineralization defect, and accumulation of unmineralized osteoid (Table 1 ). the association of vitamin D deficiency, and the role of 1,25-dihydroxyvitamin D deficiency in osteomalacia in end-stage renal disease is unclear (81 ). Defective skeletal mineralization, due to the decreased vitamin D intake and, consequently, low serum 25-hydroxyvitamin D concentration has been responsible for development of osteomalacia in the United Kingdom (82) and Scandinavian countries. This deficiency is largely due to the lack of adequate sunlight exposure, and also because of unavailability of foods fortified with vitamin D. However, its occurence is expected in malnourished patients with chronic renal failure (83), in those with nephrotic syndrome (84) due to the loss of group specific protein 14

17 in urine and in chronic renal failure patients on anticonvulsants (Table 3). Table 3. Mechanisms of Vitamin D Deficiency in Chronic Renal Failure Condition Low Intake of Dairy Products and Insufficient Sun Exposure Nephrotic Syndrome and Anticonvulsants Comments Rare in US Common in UK and Scandinavian Countries Loss of Substrate (25-0HD Deficiency) The most common course of osteomalacia is intoxication with aluminum and other heavy metals associated with the treatment of end-stage renal disease (85). The epidemics of fracturing "dialysis osteomalacia" and encephalopathy were first reported in the United Kingdom (86). This incidence was initially related to hypophosphatemia and phosphorus depletion. The pathogenetic role of aluminum intoxication was suggested, following the detection of markedly increased aluminum levels in patients who died of encephalopathy (87). This finding was supported by epidemiological data showing the relationship of osteomalacia, dialysis encephalopathy, and high concentrations of aluminum in water used for dialysis. In the United States, a retrospective analysis of bone biopsy obtained in patients with end-stage renal disease and a diagnosis of osteomalacia, revealed either heavy or moderate staining for aluminum (88) (Fig. 14 ). This was found in a substantial number of patients on chronic hemodialysis. 15

18 80 Heavy CTrace 70 Medium ONo Stain 80 J 50 I 40 '0 30 ~ Flbroala Mixed Mild O.teomalacla Fig. 14. Distribution of Aluminum Stain in Uremic Bone Disease Aluminum Metabolism Aluminum intoxication in patients with chronic renal failure is commonly related either to the use of aluminum-contaminated dialysis fluid or ingestion of aluminumcontaining phosphorus binding drugs (Fig. 15) (89). Avoidance of aluminum-contaminated water in dialysis process as well as preferred prescription of aluminum-free phosphorus binders have greatly diminished the prevalence of aluminum-related bone disease (12). However, some degree of aluminum accumulation resulting in subtle or overt toxicity may persist in certain number of dialysis patients. This finding is largely related to intestinal absorption from low doses of aluminum-containing phosphorus binders and from dietary sources (90). Intestinal absorption of aluminum has been shown to be influenced by several factors. Citrate and other complexing agents, young age, diabetes and uremic state itself have been shown to increase bioavailability and intestinal absorption of aluminum (91 ). In particular, iron deficiency has been suggested to promote the intestinal absorption of aluminum (92). This finding would be of general importance in view of the increasing prevalence of absolute or functional iron deficiency related to widespread use of human recombinant erythropoietin in patients with chronic renal failure. In this case serum aluminum is bound to transferrin and cellular uptake of aluminum is mediated by transferrin receptors. However, because no transferrin receptors are expressed on the absorptive surface of small intestinal epithelial cells, the notion is doubtful (Fig. 15). 16

19 Normal Renal Function E.S.R.F. In Dialysis Urinary Excretion j.l.g/day Fecal Excretion I ,000 ~r 1 No Urinary Excretion Fig. 15. Aluminum Metabolism Pathophysiologic Mechanisms of Aluminum-Related Bone Disease The exact mechanism(s) by which aluminum inhibits bone mineralization has not been identified. However, in experimental animals parenteral aluminum adminstration has been shown to inhibit bone mineralization (93). Aluminum intoxication causes defective mineralization and long-term inhibition of osteoblast differentiation, but increased matrix synthesis by existing osteoblasts (Fig. 16). 17

20 1. AI effect on osteoblast 2. AI effect on PTH 3. AI effect on r AI Fig. 16. Pathogenesis of Aluminum-Induced Bone Disease The high aluminum concentrations have been shown to inhibit osteoblastic cell proliferation, and bone phosphatase activity (94,95). In addition, aluminum decreased the stimulatory action of PTH on proliferation of osteoblastic precursor cells and bone phosphatase activity, resulting from reduced PTH secretion (12) and bone PTH receptors (96). An inverse relationship between osteoblast number and bone aluminum has been shown in long-term dialysis patients with aluminum-associated bone disease (Fig. 17). Aluminum, at a high concentration, may also inhibit mineralization by osteoblastic independent mechanisms, reducing amorphous calcium phosphate transformation and hydroxyapatite crystal growth (97). The incomplete disappearance of osteomalacia after removal of aluminum indicates that other factors such as 25-hydroxyvitamin D deficiency, are involved in this form of osteodystrophy. 18

21 , s C!)C!l u 4.0 c3-t! -- u::s 2.0 ;:U) enmm 1.0 '8.2.!~ 0.4 en Stainable Bone Aluminum (% Total Surface) r = -.82 p<.001 n= Fig. 17. Relationship Between Osteoblastic Osteoid and Stainable Bone Aluminum in long-term Dialysis Patients Adynamic Bone Disease (Low Turnover Bone Disease) "Adynamic" or "aplastic" bone disease has been demonstrated to occur with increasing frequency in dialysis patients (10,12). It has been detected in 60% of patients undergoing peritoneal dialysis and 36% of patients on chronic hemodialysis (1 0). This entity is characterized by a significantly low bone formation and without osteoid accumulation (12) (Table 1). The latter characteristic distinguishes aplastic bone disease from osteomalacia. Adynamic bone disease is encountered both in secondary and idiopathic forms. In its secondary presentation, adynamic bone disease is encountered most commonly in patients with end-stage renal disease without secondary hyperparathyroidism (Table 4). These patients generally have been overtreated with calcium and vitamin D, have diabetes or aluminum intoxication. The association between continuous ambulatory peritoneal dialysis may be related to the transfer of a greater amount of calcium from dialysate to the patient and suppression of parathyroid hormone secretion that occurs with this form of dialysis as compared with hemodialysis (16) (Table 4). 19

22 Table. 4. Classification of Adynamic Bone Disease Type Description Pathogenesis Idiopathic Acellular Bone Increased Production of (No Remodeling) Suppressors of Bone Formation (IL-11, IL-4) Increased Soluble Receptors (IL-1, TNF-B) Decreased Production of Promoters of Bone Formation (BMP-7) Secondary Acellular (No Remodeling) Decreased PTH Secretion Cellular Mechanism Involved In Secondary Form Parathyroid hormone is the best known factor that increases bone formation (98-100). PTH administration induces bone formation, in part due to its ability to increase the pool of osteoblast precursors (98). Hypersecretion of PTH may thus be required to maintain normal rate of bone formation and bone remodeling in patients with end-stage renal disease (11,12,17) (Fig. 12). Parathyroid hormone also increased the production of insulin-like growth factor-1 by osteoblasts in vitro (101) and in vivo (102). Adynamic bone disease in patients with end-stage renal disease with normal parathyroid hormone function suggests that production of one or more inhibitors of bone formation is increased or that promoters of bone formation (growth factors) are reduced. It has been shown that activation of the immune mechanism from dialysis may be responsible for the production of some of these inhibitory factors (71,72). These factors include, interleukin-11 and interleukin-4, which may inhibit osteoblastic bone formation ( 1 03,104 ). An inhibitory effect is also possible, if the soluble receptors or antagonists override the actions of tumor necrosis factor-a or interleukin-1 IL-1 and TNF-a are generally considered as activators of the remodeling cycle, but their soluble receptors and antagonists are increased during dialysis (105, 106). The other potential inhibitors of bone remodeling in patients with end-stage renal disease include nitrous oxide (107) and fragments of parathyroid hormone-related protein (1 08, 1 09). In addition to the inhibitors of bone remodeling, a deficiency of promoter in bone formation or growth may contribute to adynamic bone disease. Osteogenic protein 1, a potent osteoblast growth factor, is produced by normal tubular cells (110). A deficiency of 20

23 the factor may lead to the need for more parathyroid hormone. Gonadal hormonal deficiency, in both men and women with end-stage renal disease, may play an important role in development of osteopenia. Role of Metabolic Acidosis (Low Turnover Bone Disease) The association of metabolic acidosis to the pathogenesis of skeletal abnormalities in end-stage renal disease has not yet been fully studied. A net calcium efflux from bone during metabolic acidosis has been shown (111 ). A greater calcium efflux has been shown in metabolic acidosis than respiratory acidosis. The loss of bone during acidosis is attributed both to physiochemical process and cell mediated mechanism (112}. Acidosis has been shown to stimulate osteoclasts and to inhibit osteoblastic bone formation. The latter effects have been shown to occur independent of parathyroid hormone stimulation in normal subjects. But more bone loss was detected in the presence of intact parathyroid glands, due to PTH stimulation and an increased bone turnover. Patients with end-stage renal disease treated with an increased dialysate bicarbonate concentration to maintain a normal predialysis serum bicarbonate concentration at 24 meq/l, have not shown any evidence of secondary hyperparathyroidism or a progressive decrease in bone resorption. Therefore, an optimal correction of metabolic acidosis (predialysis serum bicarbonate concentration of 24 meq/l} could possibly ameliorate the progression of skeletal lesions in uremic patients. DIAGNOSIS The recognition of the specific skeletal lesion in renal osteodystrophy requires a bone biopsy to make an accurate diagnosis. However, standard clinical practice in treating patients with end-stage renal disease and renal osteodystrophy has evolved away from the performance of a diagnostic bone biopsy before initiation of therapy, because of pain associated with the procedure. Clinical Signs, Symptoms and Laboratory Features of Renal Osteodystrophy The symptoms appear late in the course of renal osteodystrophy, are rather nonspecific, and are usually subtle and insidious in their onset. The severity of symptoms often does not correlate with radiological and histological abnormalities. In addition, biochemical features can be used but are not sufficient to establish the type of osteodystrophy in an individual patient (Table 5}. 21

24 Table 5. Clinical and Laboratory Characteristics of Renal Osteodystrophy Feature Hyperparathyroidism Aluminum Toxcity (Osteitis) (Osteomalacia) Bone pain Mild Severe Proximal muscle Mild to moderate- Severe weakness Bone fracture Rare Frequent Extra skeletal calcification Common Not characteristic Serum calcium Low to high Low to high Serum phosphorus Often >6.5 mg/dl Often <5.0 mg/dl Serum alkaline Commonly twice normal Rarely twice normal phosphatase PTH (N-Terminal) >4 x normal <2 x normal Serum aluminum Baseline Often <1 00 mcg/l Rarely <100 mcg/l DFO-stimulated Increases <175 mcg/l Increases >175 mcg/l Risk factors Young age, Old age, diabetes mellitus, noncompliance PTx Though uncommon, bone pain may develop independent of skeletal disease. However, the most common cause of bone pain is osteomalacia due to aluminum intoxication. Physical findings are lacking, occasional localized tenderness may be apparent. Proximal muscle weakness is common in osteomalacia but may also occur in osteitis. This finding may be due to secondary hyperparathyroidism, abnormal vitamin D metabolism, and aluminum intoxication (114). Treatment with 25-hydroxyvitamin D and removal of aluminum with deferoxamine without vitamin D treatment have been shown to significantly improve muscle weakness. Patients with osteomalacia often have skeletal deformities and fractures. Although initial reports suggested that adynamic bone disease does not often cause symptoms ( 11, 12), an increased fracture rate has been detected with subsequent followup (115). 22

25 Periarthritis and arthritis may occur with osteitis. Treatment of secondary hyperparathyroidism with subtotal parathyroidectomy improves this symptom in a short time. Spontaneous tendon rupture may occur in patients with osteitis. Rupture occurs commonly in the quadriceps or triceps tendons (116). An abnormality in collagen metabolism affecting tendons and repeated minor fractures of the bone cortex at the site of tendon insertion may be responsible. Extra skeletal calcifications are commonly encountered in patients with osteitis. Calciphylaxis is being diagnosed more frequently in the past few years. Calciphylaxis is characterized by peripheral ischemic tissue necrosis, vascular calcifications, and cutaneous ulcerations (117). Such lesions resemble vasculitis without any evidence of fibrinoid necrosis. This syndrome had been previously considered to be a consequence of secondary hyperparathyroidism. In some instances a substantial improvement has occurred following a subtotal parathyroidectomy (118). Patients will die of sepsis without any treatment. Because of the poor prognosis, urgent partial parathyroidectomy is recommended, with evidence of severe secondary hyperparathyroidism (118). Corneal calcification frequently occurs when Ca x P product is high. The corneal calcification may be asymptomatic, or cause inflammation (''red eye" syndrome). Pruritus is a common symptom and may reflect the presence of high PTH, hypercalcemia, high Ca x P product (70 mg/dl 2 ). It may improve or totally disappear after partial parathyroidectomy (114). Serum calcium and phosphorus concentrations are not particularly helpful in distinguishing the various bone lesions. High values are expected in low or high bone turnover states, but normal values are more common. An elevated serum concentration of alkaline phosphatase (twice normal) occurs rarely in low turnover bone disease and is encountered in osteitis. Parathyroid hormone concentrations above twice normal is suggestive of osteitis (114). Normal and low normal values suggest the diagnosis of low turnover bone disease (12,14,15), but are not sufficient to establish the type of osteodystrophy in an individual patient, especially if calcitriol has been administered. Serum aluminum concentration, especially after the administration of deferoxamine, indicate the presence of aluminum-related bone disease (119). Basal serum aluminum concentrations below mcg/l exclude the possibility of aluminum intoxication. Microcytic anemia should be considered in patients with aluminum intoxication. This anemia is mild and usually can be overcome by increasing the dose of erythropoietin. In patients with end-stage renal disease and osteitis or adynamic bone disease, bone mineral density is reduced. In both of these conditions, osteopenia has been shown to be associated with fractures. However, in osteitis the increased cortical bone resorption involving long bones tends to reduce the bone mass, but in trabecular bone the 23

26 accumulation of woven bone may leave the bone mass unchanged, despite a decrease in lamellar bone. Thus, the measurement of bone mineral density does not correlate well with bone strength due to the presence of dystrophic calcification and the accumulation of woven bone (mineralized, nonlamellar, immature bone) which is qualitatively poor. Therefore, bone mineral density may not assist in establishing the diagnosis and assessing the tendency for bone fractures. PREVENTION AND MANAGEMENT OF RENAL OSTEODYSTROPHY The objectives of the clinical management of renal osteodystrophy include 1) control of serum calcium and phosphorus concentration; 2) prevention of parathyroid gland hyperplasia or, if has occurred, suppress PTH secretion and reduce parathyroid gland hyperplasia; 3) reduce exposure to aluminum; and 4) reverse the skeletal abnormality (Table 6). Table 6. Prevention and Treatment of Renal Osteodystrophy Prevent Phosphorus Retention Optimize PTH Secretion Reduce Exposure to Aluminum Prevention of Phosphorus Retention and Hyperphosphatemia Hyperphosphatemia is not detected until renal function falls 20 to 30% below normal (120). It has been shown that serum phosphorus concentration varies widely in these patients, and is most affected by dietary phosphorus intake. Intestinal absorption of phosphorus is mainly passive through paracellular pathway. This process is not saturable and increases linearly with intake (121 ). It has been shown that net intestinal absorption of phosphorus is minimally reduced in patients with advanced chronic renal failure, as determined by metabolic balance studies (122) (Fig. 18) This places the patients with decreased renal function at risk for development of hyperphosphatemia. 24

27 "C 1200 y= 0.46x + 26,. r =.81,. m,. E 800,. -,.,. c,. 0,.,. ;=,....,.,. c. 600,. 0,.,. Cl),..c < Cl) z 200,.,.".r". N::~~~ Phosphorus Intake (mg/d) Fig. 18. Advanced Renal Failure Administration of a vitamin D derivative may increase an active transcellular intestinal phosphorus absorption (123}. Therefore, serum phosphorus concentration may rise after administration of vitamin D metabolites in those patients with dietary phosphorus noncompliance. The available options for prevention of phosphorus retention include 1} reducing dietary phosphorus intake, 2} preventing the absorption of phosphorus with phosphorusbinding agents, and 3} enhancing removal of phosphorus by an efficient dialysis regimen. Dietary Phosphorus Restriction Dietary phosphorus restriction is crucial in the prevention and management of uremic hyperparathyroidism. Meat and dairy products are the most important dietary sources of phosphorus. Low phosphorus diets are generally unpalatable to tastes. In addition, some patients may develop negative nitrogen balance and become protein malnourished. With the elimination of dairy products and limitation to 40 g of protein per day, the dietary intake of phosphorus ranges between mg/day, a quantity which is near 60% of normal daily phosphorus intake (124}. With institution of the maintenance dialysis, a dietary protein of approximately 1 g/kg per day is generally prescribed, the measured phosphorus intake is from 900 to 1200 mg/day. Therefore, an attainment of negative phosphorus balance and control of 25

28 hyperphosphatemia can not be achieved without the use of agents which bind phosphorus in the intestine. Phosphorus-Binding Agents (Table 7) Aluminum Compounds as Phosphate Binders. The most potent phosphate binders are hydroxide or carbonate salts of aluminum. However, aluminum has been shown to accumulate in the bone of patients with renal failure (88) when given at high doses for an extended period. Because the kidney is the major route of excretion (125), prolonged ingestion of aluminum-containing phosphate binders results in aluminum overload in patients with impaired renal function. Calcium Supplements as Phosphate Binders. Recently, calcium slats have been substituted for aluminum-binding ge!s in the treatment of patients with chronic renal failure. Theoretically, calcium supplementation might be useful in patients with impaired renal function because it could bind phosphate and impair its absorption, correct metabolic acidosis, and avert malabsorption of calcium. Such a treatment could be expected to increase serum calcium concentration, decrease serum phosphorus, and reduce serum PTH. In patients with aluminum-related bone disease, the subsitution of aluminum-containing phosphate binders with calcium carbonate has been shown to control hyperphosphatemia and to improve bone histological picture. Calcium carbonate and calcium citrate are less effective than aluminum-containing phosphate binders in controlling hyperphosphatemia. They increase the risk of development of hypercalcemia and soft tissue calcification, especially in patients who are also taking 1,25-(0H) 2 0. Calcium acetate has recently been found to be superior to other calcium salts in phosphate binding in vivo and in vitro in normal subjects (126). Such a finding has not yet been disclosed in long-term control of hyperphosphatemia in patients with chronic renal failure. However, short-term studies in patients with renal failure have shown that calcium acetate binds twice as much phosphate (relative to calcium absorbed) than does calcium carbonate (127). Previous studies have shown that a mixture of ketoanalogues and amino acids decreased serum phosphorus and serum PTH concentrations in patients undergoing longterm hemodialysis and in patients with advanced renal failure without the use of additional phosphorus binders. Recently both in vitro and in vivo studies have shown that ketoanalogues are capable of binding phosphorus in the intestinal tract. The mechanism of phosphorus binding of ketoanalogues could be expleained by their oral administration in the form of calcium salts. 26

29 Table 7. Prevention of Phosphorus Accumulation Aluminum Compounds Calcium Supplements Magnesium Salts Natural Polymeric Anion Calcium ketovaline (Ca-3-methyl-2-oxobutyrate) is one component of the ketoanalogue mixture that has been shown to be an effective phosphorus binder in longterm hemodialysis patients (128). In a short-term study, both calcium ketovaline and calcium acetate have been shown to be effective phosphorus binders without causing hypercalcemia. The use of calcium ketovaline may be limited by its high ciost and unpalatibility. Calcium carbonate has been shown to be an effective phosphate binder in about 60% to 70% of patients with chronic renal failure (129). From 4 to 12 g of calcium carbonate daily is required to prevent hyperphosphatemia. Hypercalcemia is usually a side effect of calcium carbonate treatment. In a long-term study of hemodialysis patients, a combination of dialysate with a low calcium content (2.5 meq/l) and oral calcium carbonate resulted in control of hyperphosphatemia without hypercalcemia. Calcium carbonate is tolerated well by most patients. Calcium citrate, although well tolerated, increases the risk of aluminum toxicity (130). Calcium acetate is considerably more expensive than calcium carbonate. The high cost may limit its use as a phosphate binder (Fig 19). The failure of response to calcium supplements might be attributable to dietary overindulgence in phosphate-rich foods, inadequate doses of calcium supplements, or improper time of administration. The dose of calcium salts should be adjusted to match phosphorus intake. Calcium salts should be given immediately before or after a meal, or both times at one-half the dose (131 ). In summary, a rational approach to controlling hyperphosphatemia would be to restrict dietary phosphorus to 800 mg/d and administer calcium salts. Hypercalcemia is a major side effect of calcium carbonate treatment. This risk could be reduced if a low dialysate calcium concentration (2.5 meq/l) is used with calcium carbonate. Magnesium salts as a phosphate binder. 27

30 Csldum carbonate N CX> E- 10 :I 'a ~t 0 u II li: i E II 7 I nme,months ';(' ! 110 E a it :::1. w e :_300 i! 80 E :I ~ E 40 2 j t ~ E 200,X 100 ol Al(OH), 3 Month 7 I I AI(OH), 3 Month 7 I I caco, caco, Fig. 19. Phosphate Binding by Calcium Carbonate

31 The role of magnesium salts in controlling hyperphosphatemia is controversial. Magnesium carbonate, but not magnesium oxide or trisilicate, has been shown to be an effective phosphate binder (132). However, magnesium salts should be used cautiously because they may cause hypermagnesemia and impair bone mineralization. Natural polymeric anion as a phosphate binder. Alginate phosphate binders are naturally occurring polymers of complex but defined composition (133). Each molecule contains up to 1,000 carboxylic groups and has a molecular weight of 10,000 d to 20,000 d. These substances are best described as homopolyuronic and heteropolyuronic acids. They are nontoxic. Their monomers are sugars that may be partiablly degradable by microorganisms within the intestine. For clinical application, these polymers are charged with variable but well-defined amounts of different cations. For phosphorus binding, they are charged with calcium and ferric ions. The phosphate-binding power of the polymer has been shown to be two to three times that of aluminum antacids on a weight basis. During a long-term trial (133) with calcium-charged polymer, no adverse reaction or incompatibility has been detected. Some calcium may be absorbed, depending on the prescribed dosage, the calcium content of the polymer, and the dietary phosphorus content. It is possible that cation exchange between calcium and either sodium or potassium may take place, and thus hypokalemia may ensue. Dialysance of Phosphorus It has been shown that mass transfer of phosphorus by dialysis is limited (134). The dialyzer clearance of phosphorus has been shown to be 40-50% lower than urea clearance. The amount of phosphorus removed during hemodialysis changes with the predialysis serum phosphorus concentration and the efficiency of dialyzer being used. Approximately mg phosphorus is being removed during 4 hours of hemodialysis. Therefore, in most of the dialysis patients, additional measures should be undertaken to control the phosphorus balance. Calcitriol Treatment With Vitamin D Metabolites It is known that vitamin D may be useful in the management of renal osteodystrophy. The introduction of active vitamin D metabolities has opened a new approach to the management of renal osteodystrophy. Available data suggest that altered synthesis of 1,25-(0HhD plays a key role in the pathogenesis of secondary hyperparathyroidism (28, 135). In addition, parenteral calcitriol has been shown to be an effective agent in suppressing secondary hyperparathyroidism in end-stage renal failure (136). It has been reported to significantly reduce PTH secretion (136) in patients undergoing hemodialysis with secondary hyperparathyroidism without provoking 29

32 hypercalcemia. Intravenous 1,25-(0HhD has also been reported to effectively reduce serum PTH concentrations in some patients with severe secondary hyperparathyroidism and hypercalcemia who were refractory to treatment with oral1,25-(0h) 2 D (137, 138). The pathogenetic background for the superior action of parenteral1,25-(0hhd over oral calcitriol is unclear. When given parenterally, calcitriol may exert a lesser effect on intestinal calcium absorption. Moreover, a higher peak in serum 1,25-(0HhD may be attained (139, 140) because of a lack of intestinal inactivation of 1,25-(0HhD. Higher plasma calcitriol concentrations acheived after a parenteral dose may be responsible for inhibition of pre-pro PTH synthesis (47). There is evidence that parathyroid glands have receptprs for 1,25-(0HhD and that receptors are down-regulated in renal failure (141). Moreover, there is evidence that 1,25-(0HhD acts directly on parathyroid glands to suppress the synthesis and secretion of the hormone (136, 142) (Table 8). Table 8. Comparisons of the Effects of Oral and Parenteral 1,25-(0HhD Parenteral Oral 1,25-(0H) 2 D 1,25-(0H) 2 D Calcemic effect Lower Higher Plasma concentration Higher Lower Effect on intestinal Lower Higher Ca absorption Inhibition of PTH Higher Lower secretion Despite the initial promising results of intermittent treatment with intravenous calcitriol, there appear to be few differences in the efficacy or side effects of calcitriol between the intravenous and intermittent oral administration of calcitriol ( ) in long term controlled trials. The results showed that intermittent treatment, regardless of adminstration route, is poorly tolerated largely due to the development of hypercalcemia and hyperphosphatemia, fails to reduce parathyroid gland size and funtional abnormalities, and therefore has a limited ability to acheive sustained serum PTH concentrations in endstage renal failure patients with severe hyperparathyroidism (Fig. 20). 30

33 1<100 i ~ 800 1S! 600 E <100 Calcltrtol Started!! 200 t n=:::::::ri~ 0... ~... ~~~... ~ " Time, weeks ~ 2.70 :::: ~ 2.60 E 2.50 E~ :I 2.40 u iii 2.30 CJ 2.20 E ~ 2.00 Calcltrlol Started! s 1.90 ~ _...._-'-1 -e- IV CalcllrtolfOrel Placebo -o- Pulse Oral CalcllrtoiiiV Placebo " Tlme,wuks Fig. 20. Effect of IV vs Oral Calcitriol in Dialysis Patients Over the past decade the incidence of adynamic bone disease has increased progressively with the use of parenteral calcitriol and as calcium salts have been substituted for aluminum-binding gels in the treatment of chronic renal failure (10, 12, 16). The association between adynamic bone disease with calcium and calcitriol treatment was suggested to be the result of suppression of PTH secretion (11, 12, 145). Hypersecretion of parathyroid hormone may be required to maintain normal bone formation in patients with end-stage renal disease. In addition, calcitriol-induced suppression of osteoblast proliferation may increase the risk of development of adynamic bone disease, even when serum PTH concentrations are high, possibly because of antiproliferative action of 1,25- (0HhD. An optimum serum PTH concentration in a patient with end-stage renal disease is not known. Serum PTH concentrations have been shown to probably be maintained at a level three to four times above the upper limit of normal in adults and at a higher level in children who are receiving calcitriol treatment ( 14) to avoid the development of adynamic bone disease (Fig. 21 ). 31

34 c 15 0 iii E 0 "" CD c 0 Ill 35 rr- 3o...a; " ltl!. ~A-. - ~ ~t A ;.. # Parathyroid Hormone (pg/ml).... I /--' Fig. 21. Effect of PTH on Bone Formation in Dialysis Patients Indications for Calcitriol Treatment Despite lack of desired range for serum PTH concentration in patients with endstage renal disease, a consensus conference, held in Orlando at the Annual Meeting of the American Society of Nephrology 1994, recommended that the most important factor in determining the initial dose of calcitriol is the severity of hyperparathyroidism (146). The recommendations for the parenteral use of calcitriol in patients undergoing dialysis are shown here (Table 9). Table 9. Recommendations for the Parenteral Use of Calcitriol Condition Mild-Moderate Hyperparathyroidism Moderate-Severe Hyperparathyroidism Overt Severe Hyperparathyroidism PTH pg/ml pg/ml > 1200 pg/ml Dose ~g/dialysis 2-4 ~g/dialysis The role of IV Calcitriol is Unclear PTH :s;; 200 pg/ml, Calcitriol is not indicated 32

35 It is agreed that 1 ) in patients with intact PTH levels 5-6 fold greater than upper nonnallimit, parenteral calcitriol is almost always indicated; 2) in patients with intact PTH levels 3-5 fold normal, therapy at low doses meg/dialysis is indicated. In these patients the gradual rise in serum PTH concentrations, should be definitely considered a criterion for initiation of treatment; 3) in patients with intact PTH levels of 2-3 fold nonnal, calcitriol is not indicated due to the risk of development of adynamic bone disease. The role of parenteral calcitriol treatment in severe secondary hyperparathyroidism, once PTH is greater than 1200 pg/ml, is not clear. At this stage it appears that diffuse hyperplastic glands may become nodular, with decreased numbers of vitamin D receptors. The exact pathogenetic mechanisms responsible for the treatment failure have not been yet established. The most important factor accountable for the treatment failure is hyperphosphatemia. Hyperphosphatemia is not only an important factor in increasing the Ca x P product and increasing the risk of soft tissue calcification, but in addition it directly stimulates PTH secretion. Thus, patients with severe hyperphosphatemia will not respond to parenteral calcitriol (146) (Fig. 22). 1 Inhibition of 1,25-(0H) 2 D i Hyperphosphatemia Fig. 22. The Effects of Hyperphosphatemia 33

36 Role of Other Vitamin D Analogues Due to the aforementioned limitations, the therapeutic index for calcitriol in suppressing PTH secretion is quite low. Efforts have been made to identify analogues of vitamin D that would have a suppressive effect on PTH secretion, without the development of hypercalcemia. 1 a-hydroxyvitamin D 2. Recently, it has been shown that oral treatment with 1a- hydroxyvitamin D 2 of dialysis patients is highly effective in suppressing secondary hyperparathyroidism and is safe despite exclusive use of calcium-based phosphorus-binders (147). The mechanism by which this metabolite suppresses PTH is unknown. However, it was shown that inhibition of PTH secretion occurrs prior to the rise in serum calcium concentration. It is possible that this metabolite directly suppresses PTH secretion by parathyroid cells without the development of hypercalcemia and hyperphosphatemia dihydroxwitamin D. There is no definitive evidence that 24,25-(0HhD treatment alone or in combination with 1,25-(0H) 2 D has prophylactic or therapeutic value in renal osteodystrophy (148). 22 -oxaca lcitriol. Recently, an analogue of 1,25-(0HhD, 22-oxacalcitriol (149, 150), was reported to have a profound suppressive effect on PTH secretion and calcium absorption, with little or no direct effect on bone. However, this is a dissociative effect and was not substantiated in later studies. At the present time, it is doubtful that this vitamin D analogue offers any added advantage over calcitriol treatment. Parathyroidectomy Parathyroidectomy should be undertaken as the last step in the treatment of patients with secondary hyperparathyroidism. It should always be considered after careful assessment of aluminum loading, and possibly after bone biopsy for histological verification of osteitis and exclusion of aluminum-induced bone disease. Parathyroidectomy is indicated in the presence of persistent, symptomatic hypercalcemia (after excluding the other potential causes of hypercalcemia); severe intractable pruritus; serum Ca x P product that persistently exceeds mg/dl 2 with progressive extraskeletal calcifications; and calciphylaxis and symptomatic hypercalcemia after renal transplantation (Table 10). 34

37 Table 10. Indications for Parathyroidectomy in Patients with Advanced Renal Failure Assess aluminum overload by histological examination of bone to exclude bone aluminum deposition and verify diagnosis of osteitis If above criteria are met, Parathyroidectomy is indicated in patients with: Marked Sustained Hypercalcemia Severe Intractable Pruritus Progressive Extraskeletal Calcifications Ca x P Product > 70 (mg/dl) 2 Calciphylaxis Symptomatic Hypercalcemia after Renal Transplant Three surgical approaches are used: subtotal removal, total parathyroidectomy and total parathyroidectomy with auto transplantation. Long term follow-up of patients with subtotal or total parathyroidectomy with auto transplantation has shown a high incidence of recurrent hyperparathyroidism (151 ). Recently, a reduction of parathyroid gland cellular mass by percutaneous injection of absolute ethanol under localization by ultrasound was reported. Post surgical hypoparathyroidism remains a major risk after total parathyroidectomy. Thus, administration of calcitriol and calcium is required to restore normal serum calcium levels. However, a decrease in bone turnover can occur, leading to adynamic bone disease and increased risk of soft tissue calcification. Patients may become prone to aluminum overload after parathyroidectomy (152). Administration of 1,25-(0HhD to postsurgical patients with soft tissue calcification should be avoided. In such cases, serum calcium levels should be regulated following surgery with individuallly dosed calcium. A fall in serum calcium due to the so-called "hungry bone syndrome" correlates with the severity of the skeletal disease and may be associated with hypophosphatemia and hypomagnesemia. In patients with severe skeletal disease hypocalcemia may persist for 2-3 months after parathyroidectomy. Prevention and Treatment of Aluminum Related Bone Disease (ARBD) Prevention of ARBD Aluminum accumulation, and thus aluminum-related bone disease (ARBD), may not be totally preventable in uremic patients. However, appropriate precautions can minimize 35

38 the possibility of aluminum intoxication and allow an early diagnosis of patients and dialysis centers at risk. These measures include regular monitoring of 1 )serum aluminum levels; 2) control of the water supply by analysis of aluminum concentration in tap water, reverse osmosis-treated water, and dialysis fluid (dialysis fluid aluminum concentration of ~10 mcg/l); 3) the use of aluminum-containing phosphorus binders should be minimized or be substituted by calcium salts; and 4) reduced citrate content in the diet (Table 11) Table 11. Prevention of Aluminum Related Bone Disease Methods Serum Aluminum Control Water Supply Limit the Use of AI Phosphorus Binders Reduce Citrate Content in Diet Comments Regular Serum Aluminum Analysis Dialysis Fluid Aluminum Concentration ~ 1 0 mg/l Substitute with Ca Salts Citrate Fascilitates Intestinal Aluminum Absorption In addition patients at increased risk for development of aluminum intoxication including, children, patients with diabetes mellitus and those with previous parathyroidectomies and low skeletal bone turnover should be closely monitored. Treatment of ARBD In patients with end-stage renal disease, hemodialysis with low-aluminum dialysate leads to removal of small and generally insignificant quantities of aluminum because 80% to 90% of aluminum in plasma is protein bound (153), and only 10%-20% is ultrafilterable and available by dialysis. Once aluminum intoxication has developed discontinuation of aluminum-containing antacids and dialysis against low-aluminum dialysate are not sufficient means to decrease the aluminum burden in the body. Over the past several years, deferoxamine (DFO) has been used as a chelating agent to enhance aluminum removal in aluminum overloaded patients. Deferoxamine belongs to a family of iron-binding ligands called siderophores. This drug has been used to remove iron. Deferoxal'!line is a straight-chained molecule containing three hydroxamic acid groups that attaches to ferric ion (154). It also has a binding affinity to aluminum and forms a deferoxamine-aluminum complex. Deferoxamine- 36

39 aluminum complex has a molecular weight of 620 and is small enough to be easily dialyzed through dialysis membranes. It has a high affinity and specificity for trivalent cations and low affinity for divalent cations such as calcium and magnesium. Deferoxamine enhances aluminum removal in dialysis patients by two mechanisms. First, it mobilizes aluminum from tissue stores and increases the total plasma level of aluminum. Second, it increases the fraction that is not protein bound and thus largely ultralifterable. Long-term treatment of patients with aluminum-related bone disease maintained on peritoneal dialysis or hemodialysis with deferoxamine has been shown to be effective in relieving symptoms, enhancing quality of life, and improving bone histomorphometric picture ( ). Aluminum-related bone disease should be diagnosed before long-term treatment with deferoxamine is initiated. Bone biopsy is the standard for unequivocally identifying aluminum-related bone disease; (158) it is also useful in monitoring the progress of patients on deferoxamine therapy (155). A low dose of deferoxamine (5 mg/kg) should be used for the treatment. It has been demonstrated that sufficient aluminum chelation occurs with this dosage (159). Deferoxamine treatment should be instituted in all patients with positive DFO test (6 serum Al>50 mcg/l) and a serum PTH <650 pg/ml, and any clinical signs of aluminum-related bone disease, including bone pain, pronounced muscle weakness, multiple bone fractures, a large cumulative intake of aluminum, previous parathyroidectomies or histological/histochemical evidence of aluminum-related bone disease (Fig 23). Once Weekly DFO 5 mg/kg (60 minutes IV infusion) + 1st Session Post-DFO: High Performance Extraction Procedures ll.sai below 50 mg/l Months + Stop Therapy (In asymptomatic patients) (-4 -k wash-out period) + DFO-test (5mg,1cg) Repeat DFO-test after 1 Month ll.sai below 50 ug/l + sal Monitoring II' ~ ~ t:j.sai above 50 ug/l + Second DFO Course I.-I -ll.-sai-ab-o-ve-50_u_g_/l---, + Second DFO Course Fig. 23. Strategy for the Treatment of ARBD 37

40 Deferoxamine must be administered parenterally since less than 15% of the oral dose is absorbed (159). The dose of DFO should be administered intravenously once weekly during the last hour of hemodialysis in order to allow maximal chelation (159). The removal of aluminoxamine using conventional dialyzer is modest. However, removal can be increased significantly with the addition of a charcoal hemoperfusion column or with the use of high efficiency dialyzer using high-flux polysulphone dialyzer ( 160). With these interventions, approximately 80% of both total aluminoxamine and ferrioxamine can be removed by a single dialysis from the body. The latter mode of treatment provides safety due to the rapid elimination of ferrioxamine from extracellular component. Serious side effects with deferoxamine are rare, the most common being hypotension. Altered vision precipitation of aluminum-related encephalopathy, night blindness and scotoma have been reported with the long-term DFO infusion (161 ). Deferoxamine has been implicated in the development of a number of fungal (Rhizopus) and bacterial (Yersinia) infections (161 ). However, it has not been shown to increase the risk of bacteremia in patients undergoing hemodialysis. However, these side effects have been shown to occur with deferoxamine varying between 30 and 80 mg/kg, and are rarely expected with the low dosage of 5 mg/kg. Treatment of Adynamic Bone Disease The initial reports indicated that adynamic bone disease does not often cause symptoms (11, 13). However, it has now been shown that the disease is associated with an increased fracture rate and an increased mortality rate, as compared to the patients with other renal osteodystrophy (162). Microfracture may occur with bone pain in patients with osteopenia due to adynamic bone disease. The treatment of adynamic bone disease ideally should be directed at regulating the factors which are responsible for the suppression of the bone remodeling, and at the stimulation of the factors which are involved in bone formation. It is advisable to prevent excessive suppression of PTH. PTH is one of the factors known to stimulate bone formation (98-100). PTH induces bone formation, in part, because of its ability to increase the pool of osteoblast precursors (98). PTH also increases the production of insulin-like growth factor 1 by osteoblasts in vitro (1 02) and in vivo (1 01 ). A practical guideline for the treatment of these patients includes, treatment with a dialysate calcium of 2.5 meq/l or even lower and prevention of excessive suppression of PTH (intact PTH lower than 2 to 3 fold the upper limit normal). Some of these patients treated with low calcium dialysate concentration, have shown an increase in serum PTH levels, and an increase in the bone formation rate (12). 38

41 FUTURE DIRECTIONS IN MANAGEMENT OF RENAL OSTEODYSTROPHY It is clear that the range of disorders responsible for renal osteodystrophy have been recognized. The recognition of the physiology of bone remodeling in relation to the actions of cytokines and growth factors will increase our understanding of pathophyisology of renal osteodystrophy. The development of this concept may lead to improved approaches in the prevention and treatment of renal osteodystrophy. Our previous approaches to the prevention and treatment of renal osteodystrophy have not been totally successful. In view of the inability of calcitriol to effectively treat hyperparathyroidism in many patients, newer vitamin D analogues and/or calcimimetic agents, which can reduce PTH secretion without increasing serum calcium, and optimal phosphorus-binders, may offer exciting potential new therapies for management of renal osteodystrophy. In the remaining discussion I would like to present some of the preliminary data obtained from development of new drugs in this field. Phosphorus-Binder Poly[allylamine hydrochloride] (RenaGel ). Dietary phosphorus restriction and oral administration of calcium and aluminum salts have been the principal means of controlling hyperphosphatemia in patients with endstage renal disease over the past decade. Although relatively well-tolerated, a large fraction of patients treated with calcium salts develop hypercalcemia and metastatic calcification (163). This is particularly true when administered concurrently with calcitriol despite a lowering of the dialysate calcium concentration. Therefore, a non-calcium and non-aluminum phosphorus-binder may be advantageous. Cross-linked poly[allylamine hydrochloride] (RenaGej ) is a cationic polymer that binds phosphorus anions through ion exchange and hydrogen binding. In vitro, 1 g of RenaGel binds 5 mmol of phosphorus at ph 7. In normal subjects the phosphorus binding ability of the drug was demonstrated by a fall in urinary phosphorus excretion (164). RenaGel was found to be as effective as calcium carbonate or acetate as a phosphorus-binder when used in double-blind trial of 36 maintenance hemodialysis patients followed over an 8 week period. There was no change in serum calcium concentration, but a significant fall in serum total cholesterol and low-density lipoprotein, RenaGeJ was safe, without any side effect. Thus it may be an effective alternative to oral calcium for the management of hyperphosphatemia in end-stage renal disease. (NPS R-568) A First Generation Calcimimetic Agent It has been recently shown that extracellular calcium-ion concentrations modulate parathyroid function, at least in part, through a calcium-sensing receptor on the cell surface (60) that signals the cell to alter its intracellular calcium level. 39

42 It has been demonstrated that calcium-receptor numbers are significantly reduced in parathyroid glands of uremic patients (65). NPS R-568 is a novel compound that acts as an agonist at the calcium-receptor (calcimimetic), suppresses PTH release and stimulates calcitonin secretion. Thus, it will be a potentially novel therapeutic approach for hyperparathyroidism. It has been shown that the calcimimetic agent in phase-1 trial was effective in hemodialysis patients with mild hyperparathyroidism. Seven patients received low dose (40 or 80 mg), and later a high dose (120 or 200 mg) 4 hours prior to hemodialysis for 2 days. The results showed a sustained significant reduction of PTH secretion (51%) and a significantly elevated calcitonin secretion. This study concluded that NPS R-568 rapidly lowers PTH secretion and sustains PTH suppression in uremic patients without any change in serum calcium concentration. The trend for increased calcitonin levels may provide for an additional bone anti-resorptive action independent of the lowered PTH secretion (166). In experimental animals with chronic renal insufficiency, when NPS R-568 was given orally, it had beneficial effects by increasing bone mass and bone formation rate. The intermittent lowering of the elevated PTH levels in this mode of treatment was suggested to mimic the anabolic effects on bone of exogenously administered PTH (167). Bisphosphonate Effects in Treatment of Renal Osteodystrophy Treatment for end-stage renal disease activates the immune system and production of numerous lymphokines responsible for activation of bone remodeling in renal osteodystrophy (71, 72, 105, 1 06). Bisphosphonates are synthetic pyrophosphate analogs than can inhibit osteoclastic bone resorption and, therefore, are used for the treatment of bone disease, such as tumor-induced hypercalcemia and osteoporosis (168). Recently, macrophage-suppressive and, consequently, anti-inflammatory properties of these drugs have gained more interest. Bisphosphonates inhibit some of the proinflammatory cytokine secretion (IL-1 and IL-6 and TNF-a) by activated macrophages in vitro (169). The expression of these cytokines are increased in end-stage renal disease (3-6). In addition to cytokines, bisphosphonates can inhibit the production of nitric oxide by activated macrophage in vitro (170). The production of nitric oxide has been shown to be increased in uremia. The clinical effects of these compounds and other synthetic inhibitors of nitrous oxide in the treatment of patients with end-stage renal disease and secondary hyperparathyroidism has not yet been established. 40

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