Adynamic Renal Osteodystrophy
Authors: ISIDRO B. SALUSKY, WILLIAM G. GOODMAN
Journal: Journal of the American Society of Nephrology (2001)

In recent years, adynamic renal osteodystrophy has become a common skeletal lesion in adult patients with chronic renal failure (1,2,3). More than 40% of adults who are treated with hemodialysis and more than 50% of those who are treated with peritoneal dialysis have bone biopsy evidence of adynamic renal osteodystrophy (1). The disorder is less common in children and adolescents with end-stage renal disease (ESRD), in whom it affects approximately 15 to 20% of those who are treated with dialysis (4,5,6). The long-term consequences of adynamic bone remain uncertain. It may represent simply a state of diminished bone formation and turnover in patients with ESRD that is due largely to specific components of clinical management, including oral calcium supplementation and treatment with vitamin D sterols. There is evidence, however, that adynamic renal osteodystrophy may contribute to certain adverse long-term consequences of chronic renal failure, such as the high rate of skeletal fractures that is seen in patients with ESRD (7,8). Also, the development of adynamic bone during the treatment of secondary hyperparathyroidism with large intermittent doses of calcitriol can aggravate growth retardation in prepubertal children who undergo peritoneal dialysis (9). The discussion that follows provides an overview of the pathogenesis, diagnosis, and clinical consequences of adynamic renal osteodystrophy. Consideration also is given to specific interventions that have been considered for the clinical management of adynamic renal osteodystrophy. Definition of Adynamic Renal Osteodystrophy Adynamic renal osteodystrophy represents one of a range of histopathologic lesions of bone that are found in patients with chronic renal failure and differs markedly from the skeletal lesions of secondary hyperparathyroidism (10,11). Definitive proof that adynamic bone is present in an individual patient requires bone biopsy and histomorphometric analysis. Adynamic bone is characterized histopathologically by an overall reduction in cellular activity in bone. Both the number of osteoblasts and the number of osteoclasts are diminished (Figure 1). There are relatively few sites of active new bone formation, and this change explains why the amount of osteoid, or unmineralized bone collagen, is either normal or reduced when bone biopsies from patients with adynamic renal osteodystrophy are evaluated by quantitative histomorphometry. Both the rate of collagen synthesis by osteoblasts and the subsequent mineralization of bone collagen are subnormal, but each process proceeds at a similar rate. Thus, unlike osteomalacia, in which mineralization lags behind collagen synthesis, leading to the accumulation of excess osteoid and to increases in osteoid seam width, mineralization keeps pace with or slightly exceeds the rate of collagen deposition by osteoblasts in adynamic renal osteodystrophy. As a result, the width of osteoid seams is normal or diminished in the adynamic lesion.Figure 1: . The histologic appearance of adynamic renal osteodystrophy. There are few, if any, osteoid and resorption lacunae. There is a paucity of cells along trabecular bone surfaces.The rate of bone formation either is subnormal or cannot be measured by use of the technique of double tetracycline labeling in iliac crest bone biopsy specimens obtained from patients with adynamic bone (4,10,11,12). Such measurements provide a definitive distinction between patients with adynamic lesions and those who have normal or elevated rates of bone formation and turnover. Histologic changes of secondary hyperparathyroidism are distinctly absent. There is no peritrabecular or marrow fibrosis, and the both number of sites of osteoclastic bone resorption and the number of osteoclasts are reduced. Historical Perspective of Adynamic Renal Osteodystrophy Adynamic renal osteodystrophy originally was described as a manifestation of bone aluminum toxicity (13). Patients with the disorder often had symptoms of bone pain, muscle pain, and muscle weakness, and bone biopsies documented substantial bone aluminum deposition as measured by flameless atomic absorption spectrometry and by histochemical staining techniques. The histologic features of adynamic bone caused by bone aluminum deposition differed strikingly from those of osteomalacia, which was the other common skeletal manifestation of bone aluminum toxicity during the era of aluminum-related bone disease (11,13,14,15). Strictly speaking, the histologic features of adynamic renal osteodystrophy were no different from those found in patients with idiopathic or surgically induced hypoparathyroidism. They also were similar to those seen in some patients with diabetes mellitus, in patients with steroid-induced or age-related osteoporosis, and in individuals who had been immobilized (11). Thus, adynamic bone is a skeletal lesion that can arise from a variety of causes (Table 1).Table 1: Causes of adynamic renal osteodystrophyDespite an overall decline in the prevalence of aluminum-related bone disease in patients with ESRD, adynamic bone has become a much more common manifestation of renal osteodystrophy during the past 10 to 15 yr (1,2,3,16). In contrast to earlier experience, most patients with adynamic renal osteodystrophy currently do not have evidence of aluminum deposition in bone. Adynamic renal osteodystrophy without evidence of bone aluminum deposition was first described in pediatric patients who were undergoing peritoneal dialysis (4). These patients were managed with dialysate that contained a relatively high calcium concentration of 3.5 mEq/L, and they also used calcium carbonate almost exclusively as a phosphate-binding agent (4). Adynamic renal osteodystrophy without bone aluminum deposition was reported subsequently in adult patients who were undergoing hemodialysis and also were given calcium carbonate as the primary means for controlling phosphate retention and hyperphosphatemia (17). The rise in the prevalence of adynamic renal osteodystrophy in patients with ESRD corresponded temporally to the increased use in the mid-1980s of large oral doses of calcium as a phosphate-binding agent, the widespread use of large intermittent doses of calcitriol to treat secondary hyperparathyroidism, and treatment with peritoneal dialysis (18,19,20,21,22,23,24,25,26,27,28,29,30,31). Although calcium supplementation and treatment with vitamin D probably both contribute, nearly half of the patients who were evaluated in one recent report by bone biopsy when regular dialysis was begun had histologic evidence of adynamic bone, although none had been treated previously with vitamin D (2). Furthermore, calcium carbonate therapy was more effective than aluminum hydroxide in the control of secondary hyperparathyroidism during oral daily calcitriol therapy in patients who were undergoing peritoneal dialysis (32). Overall serum calcium levels were higher in patients who were treated with calcium carbonate (32). Such findings emphasize the role of calcium as an important modifier of osteoblastic activity and bone formation in patients with chronic renal failure. Another development that accounts for the relative abundance of adynamic renal osteodystrophy in the contemporary dialysis population is the increase in the proportion of older people who are treated with dialysis and who may coincidentally have postmenopausal or age-related osteoporosis (33). The number of patients with diabetes mellitus who are undergoing regular dialysis also continues to rise. These individuals can have adynamic bone due to diabetes per se, or they may be predisposed to developing adynamic lesions during the longterm clinical management of chronic renal failure (31). Pathogenesis of Adynamic Renal Osteodystrophy Reductions in osteoblastic activity and bone formation are the hallmarks of adynamic renal osteodystrophy. These changes can be due either to direct and specific inhibitory effects of systemic factors on osteoblastic function or to indirect changes in osteoblastic activity mediated through parathyroid hormone (PTH)—dependent mechanisms (34). In some cases of adynamic bone, osteoblastic function improves over time, and the disorder can be considered to be reversible (35). In other cases, impairments in osteoblastic activity persist, and bone formation and turnover cannot be restored to normal with currently available therapeutic interventions. Disorders that are associated with long-standing or irreversible reductions in osteoblastic activity and bone formation include age-related or postmenopausal osteoporosis, steroid-induced osteoporosis, idiopathic or surgically induced hypoparathyroidism, and diabetes mellitus (11). The histologic features of bone in these clinical disorders cannot be distinguished from those of adynamic renal osteodystrophy unless there is concurrent evidence of a reduction in cancellous bone volume on bone biopsy. If trabecular bone loss is present, then osteoporosis rather than renal osteodystrophy is an equally plausible explanation for low levels of osteoblastic activity and bone formation. Patients with diabetes mellitus typically have less biochemical evidence of secondary hyperparathyroidism as judged by the serum levels of PTH and alkaline phosphatase, compared with those who have ESRD as a result of other causes (36,37). As such, adynamic skeletal lesions are seen in a larger proportion of people who have diabetes mellitus as well as chronic renal failure (31,37,38). Insulin deficiency or tissue resistance to the actions of insulin may contribute to reductions in osteoblastic function and to low rates of bone collagen synthesis in patients with diabetes mellitus (39,40). Whether improvements in the metabolic control of diabetes favorably affect bone formation and turnover in patients with adynamic skeletal lesions that stem from diabetes mellitus remains uncertain. Beneficial effects of insulin therapy on bone formation have been reported, however, in experimental animals with streptozotocin-induced diabetes (40). Reversible causes of adynamic renal osteodystrophy include lesions that develop after subtotal parathyroidectomy in patients with ESRD, lesions due to bone aluminum toxicity, and those due to disorders that arise from the use of large doses of calcium-containing medications, vitamin D, and elevated dialysate calcium concentration in patients who are undergoing peritoneal dialysis (11,14,31,35,41. Adynamic bone as a result of surgically induced hypoparathyroidism may resolve in patients with ESRD if secondary hyperparathyroidism recurs and if serum PTH levels rise substantially from values determined during the immediate postoperative period. Under these circumstances, increases in bone formation and turnover reflect the trophic actions of PTH on osteoblastic and osteoclastic activity. Aluminum can be mobilized from bone, and its removal during dialysis can be markedly enhanced during treatment with the chelating agent deferoxamine (42). In the past, deferoxamine often was used to treat patients with advanced aluminum-related bone disease (43). In less severely affected individuals, the withdrawal of aluminum-containing medications was sufficient to permit the gradual mobilization of aluminum from bone and other tissues (19). Serum PTH levels rose, and bone formation subsequently increased as the extent of bone aluminum deposition diminished over time (41). Aluminum adversely affects the differentiated function of osteoblasts, and it also inhibits osteoblastic proliferation both in vivo and in vitro (44,45). A portion of the inhibitory action of aluminum on the proliferation of osteoblast-like cells is mediated directly, whereas some of the decrease in osteoblastic activity in vivo may be due to aluminum-induced decreases in PTH secretion. In this regard, aluminum inhibits PTH release from dispersed parathyroid cells in vitro (46), and serum PTH levels are normal or only minimally elevated in many patients with adynamic renal osteodystrophy due to bone aluminum deposition. Although bone formation initially may be markedly reduced in patients with adynamic renal osteodystrophy due to bone aluminum deposition, osteoblastic activity and bone formation generally increase as aluminum-related bone disease resolves (41). In contemporary clinical practice, the major contributors to the development of adynamic bone in patients who are undergoing dialysis are treatment with large oral doses of calcium, the therapeutic use of vitamin D sterols, the dialysate calcium concentration, and peritoneal dialysis (31). With regard to calcium supplements, patients with ESRD often ingest large amounts of calcium orally as phosphate-binding agents (18,19,20,21,22,23). The doses required to manage phosphate retention effectively typically exceed the 1500 mg/d that is recommended for people in the general population to prevent age-related bone loss, and the daily amount of elemental calcium ingested often ranges from 3 to 8 g (47). Although the active vitamin D—dependent component of intestinal calcium transport is reduced in patients who have renal failure and are not receiving vitamin D sterols (48), passive, or diffusional, intestinal calcium transport increases as a function of the amount ingested. Thus, substantial amounts of calcium gain entry into the extracellular fluid from the gastrointestinal tract in many patients with ESRD. As a result, episodes of hypercalcemia occur in 20 to 40% of patients who use either calcium carbonate or calcium acetate as phosphate-binding agents (32,49). Serum calcium concentrations, on average, are higher in patients with adynamic bone than in those with other histologic subtypes of renal osteodystrophy (1,5). This finding is primarily attributable to the large amounts of calcium ingested orally each day, and a high dietary calcium intake has been shown to induce sustained reductions in serum PTH levels even without measurable changes in serum calcium concentration. It is likely, therefore, that the sustained intake of large amounts of elemental calcium is a key determinant of the higher serum calcium concentrations and the lower serum PTH levels that characterize adynamic renal osteodystrophy. In addition, a reduced bone buffer capacity in patients with adynamic bone, compared with other forms of renal osteodystrophy, may have an additional role in the pathogenesis of hypercalcemia (50). The use of vitamin D sterols to treat secondary hyperparathyroidism can lead to the development of adynamic renal osteodystrophy, particularly in patients who also are given large oral doses of calcium to manage hyperphosphatemia (28,30). Adynamic skeletal lesions can develop when serum PTH levels are lowered too far during calcitriol therapy, typically to values that are associated with adynamic bone in patients who are not receiving vitamin D therapy. Oversuppression of serum PTH levels can occur during treatment with either oral, intraperitoneal, or intravenous doses of calcitriol (28,30,51). In this context, reductions in bone formation and turnover reflect PTH-dependent changes in skeletal remodeling. Calcitriol may, however, have inhibitory effects on osteoblastic proliferation and differentiated osteoblastic function that modify skeletal remodeling directly (28,30). Some patients who are treated with large intermittent doses of calcitriol to manage secondary hyperparathyroidism develop bone biopsy evidence of adynamic renal osteodystrophy, despite persistently high serum PTH levels. Such findings indicate that bone formation and turnover can be altered by PTH-independent mechanisms in patients who are actively treated with large thrice-weekly doses of calcitriol (28,30), the therapeutic approach most commonly used in patients who are undergoing long-term hemodialysis. The skeletal effects of the new vitamin D analogs have yet to be defined in humans. However, studies in dogs with renal failure demonstrated that oxacalcitriol corrects secondary hyperparathyroidism without induction of low bone turnover (52). Clinical, Biochemical, and Diagnostic Features of Adynamic Renal Osteodystrophy Patients with bone biopsy—proven adynamic renal osteodystrophy that is not due to bone aluminum deposition generally have fewer musculoskeletal symptoms, compared with those who have established secondary hyperparathyroidism. Muscle pain and muscle weakness are less common, and a smaller percentage of patients have complaints of bone pain and/or joint stiffness, which are frequent manifestations of hyperparathyroid bone disease (11). As was noted previously, basal serum calcium levels generally are higher in patients with adynamic bone than in those with other histologic subtypes of renal bone disease. Episodes of hypercalcemia also are more common in patients with adynamic renal osteodystrophy, particularly in those who use large oral doses of calcium to control serum phosphorus levels (1,5). Whether these disturbances increase the risk of vascular and soft-tissue calcification remains uncertain. The levels of PTH determined with the double-antibody immunoradiometric assay (IRMA) in serum or plasma are only modestly elevated in patients who have ESRD and adynamic renal osteodystrophy, and values may fall within the range of normal for people with normal renal and parathyroid gland function (1,5,14). As such, patients with adynamic bone have biochemical evidence of relative hypoparathyroidism, compared with other patients who have ESRD. When measured by use of IRMA assays, serum PTH levels usually are <150 pg/ml, and they often are below 100 pg/ml (normal range, 10 to 65 pg/ml) in patients who are not being treated with vitamin D and in those who are given small daily doses of calcitriol. The positive predictive value for adynamic bone increases when PTH levels are combined with measurements of serum total calcium in pediatric patients who are treated with peritoneal dialysis (5). Thus, a PTH value of <200 pg/ml, together with serum calcium value of >10 mg/ml, has a postive predictive value of 60% for adynamic renal osteodystrophy. A serum PTH level of <150 pg/ml combined with a serum calcium level of >10 mg/ml has an even greater predictive value for adynamic renal osteodystrophy, exceeding 82% (5). Such predictors are different during intermittent calcitriol therapy (30). Similar thresholds for PTH levels have been described in adult patients who were treated with maintenance dialysis (1,5,53,54,55). Thus, both in children and in adults, serum PTH levels measured with the intact assay that are two times higher than the upper limit of normal for subjects with normal renal function are associated with reduced rates of bone formation. Most current available information about the relationship between serum PTH levels and bone histology in patients with ESRD has been generated by use of IRMA PTH assays (1,5). There is evidence, however, that several widely used IRMA PTH assays cross react with large carboxyterminal, presumably biologically inactive, PTH-derived peptides, such as PTH-(7-84), as well as with full-length, biologically active PTH-(1-84) (56). By contrast, one recently developed IRMA PTH assay is highly specific for full-length PTH-(1-84), and it does not cross react with PTH-(7-84). Plasma PTH values in patients with ESRD invariably are lower when measured by use of the newer more highly specific IRMA assay for PTH-(1-84), compared with values obtained with conventional IRMA PTH assays (57). The disparity between plasma PTH levels measured by these assays ranges from 40 to 80% (57,58). Such findings suggest a potential explanation for disparities between specific levels of PTH in plasma and the corresponding histopathologic changes in bone in some patients with renal osteodystrophy 28,30,59). Variations in the relative amount of PTH-(7-84) or other biologically inactive PTH peptides, perhaps influenced by the prevailing level of ionized calcium in blood or by the administration of vitamin D sterols, may explain erroneously high plasma PTH concentrations in patients with normal or reduced rates of bone formation, as judged by histomorphometric assessment when hormone levels are measured by use of older IRMA PTH assays. Such differences in assay methodology also could account for the finding of histopathologic evidence of adynamic bone in patients with persistently high PTH levels during the treatment of secondary hyperparathyroidism with large intermittent doses of calcitriol (28,30). There is virtually no published information about the diagnostic value of other noninvasive biochemical markers of bone remodeling as predictors of bone histology in patients with ESRD. Measurements of bone-specific alkaline phosphatase, osteocalcin, and N-telopeptide in serum, which are useful in the evaluation of patients with osteoporosis in the general population, are of limited value in patients with renal osteodystrophy (60). Long-Term Consequences of Adynamic Renal Osteodystrophy The long-term consequences of adynamic renal osteodystrophy have yet to be determined, but several adverse events have been associated with the disorder. Hypercalcemia is relatively common in patients with adynamic bone, and some reports suggest that low-turnover skeletal lesions contribute to the development of soft-tissue and vascular calcification, presumably via disturbances in the regulation of serum calcium and/or phosphorus levels (61). Atsumi et al. (7) demonstrated that the prevalence of vertebral fracture is greater in adult male patients who are undergoing hemodialysis and have relatively low serum PTH levels. In one such study of 187 patients, the risk of vertebral fracture was 22% greater in those whose PTH values were in the lowest tertile (7). Such findings are of concern because skeletal remodeling is considered to be important for the repair of microfractures and for maintaining the material properties of bone (62). More recently, Coco et al. (8) described an increased incidence of hip fractures in patients who were undergoing dialysis and had serum PTH levels consistent with adynamic renal osteodystrophy. Furthermore, the 1-yr mortality rate after hip fracture was higher in patients who were undergoing dialysis, compared with patients who were undergoing dialysis and did not have fractures (8). Whether bone formation and turnover is reduced sufficiently to disrupt microfracture repair and the maintenance of skeletal integrity in adynamic renal osteodystrophy is not known, but these findings provide evidence that a relative state of hypoparathyroidism may have adverse effects in adult patients who are treated with maintenance dialysis. Additional work is needed to understand further the full impact of adynamic renal osteodystrophy on the preservation of bone mass and the risk of skeletal fracture in patients with ESRD. In prepubertal children, linear growth diminished and growth retardation worsened in those who developed adynamic renal osteodystrophy during the treatment of secondary hyperparathyroidism with large intermittent doses of calcitriol (9). In addition, diminished linear growth, delayed ossification, and reduced osteoclastic activity were observed in a model of adynamic bone in rats with renal failure (63). Thus, calcitriol therapy in younger children may adversely affect the proliferation and maturation of epiphyseal growth plate chondrocytes at the ends of long bones, which leads to impaired endochondral bone formation and reduced linear growth. Preliminary results that used in situ hybridization in specimens of epiphyseal growth plate cartilage obtained from the anterior iliac crest of children with adynamic renal osteodystrophy are consistent with this concept. Thus, the levels of expression of mRNA for type X collagen, a marker of hypertrophic chondrocytes, seem to be lower in patients with adynamic bone than in those with secondary hyperparathyroidism (64). If supported by additional studies, the results in pediatric patients with ESRD suggest that the rate of transition of proliferating chondrocytes into hypertrophic chondrocytes be diminished in the adynamic lesion of renal osteodystrophy. Management of Adynamic Renal Osteodystrophy Because treatment with calcitriol and the use of large oral doses of calcium both have been implicated as causes of adynamic renal osteodystrophy, greater caution should be used in the therapeutic use of these agents in patients with ESRD. Lowering serum PTH levels to values that have been associated with adynamic skeletal lesions should be avoided when treating secondary hyperparathyroidism in those who are undergoing regular dialysis. Indeed, marked reductions in serum or plasma PTH levels over several weeks or only a few months can diminish bone formation substantially, which results in episodes of hypercalcemia (28,30,51). More gradual reductions in serum PTH levels may avert this complication during treatment with calcitriol or other vitamin D sterols. Doses of vitamin D should be lowered when PTH (intact assay) levels have approached but not yet reached the therapeutic target range (150 to 200 pg/ml) to diminish the risk of oversuppressing PTH secretion and inducing an adynamic skeletal lesion. Monthly measurements of PTH levels are recommended for monitoring therapy adequately for patients who are actively treated with vitamin D sterols. Because serum PTH levels are normal or only modestly elevated in patients with adynamic renal osteodystrophy, the use of vitamin D sterols in such patients should be avoided (1,28). If adynamic bone develops during the treatment of secondary hyperparathyroidism with calcitriol or other vitamin D sterols, then doses should be reduced or withheld temporarily. Serum PTH levels should be repeated, however, 2 to 4 wk after vitamin D therapy is stopped, because values increase abruptly in many patients with established secondary hyperparathyroidism when vitamin D therapy is withdrawn (65). Beyond their role in the pathogenesis of adynamic renal osteodystrophy, calcium-containing, phosphate-binding agents have been implicated in recent reports as contributors to vascular and soft-tissue calcification in patients who are undergoing long-term dialysis (61,66,67). Such studies have demonstrated an association between the dose of calcium ingested and several vascular abnormalities, including calcification, intimal thickening, and diminished wall compliance (66,67). Because patients with ESRD cannot excrete excess calcium that is absorbed from the gastrointestinal tract in the urine, total body calcium balance may become markedly positive if large amounts of calcium continue to be ingested regularly (49). In light of these developments, the use of very large doses of calcium carbonate and/or calcium acetate as phosphate-binding agents should be curtailed and alternative approaches to controlling serum phosphorus levels should be developed. Despite these considerations, most renal diets contain only limited amounts of dairy products, in an effort to restrict phosphorus intake. As such, they also contain inadequate amounts of calcium. To avoid dietary calcium deficiency, patients who are undergoing dialysis should have oral calcium intake maintained at levels recommended for the general population through provision of modest supplemental amounts of calcium to achieve an intake of elemental calcium in the range of 1200 to 1500 mg/d (47). Some or all of this calcium can be given with meals as part of a phosphate-binding therapeutic regimen. Strong consideration must be given, however, to the use of phosphate-binding agents that do not provide an additional source of calcium beyond that required for daily nutritional needs. Sevelamer hydrochloride is a calcium-free, aluminum-free ion-exchange resin that binds phosphorus in the intestinal lumen and prevents its absorption. As such, it represents an alternative approach to the management of phosphate retention in patients with chronic renal failure, without the risks associated with the protracted use of large oral doses of calcium- or aluminum-containing compounds (68,69,70). Because clinical experience with this compound is limited, further assessments are needed to confirm its safety and efficacy with long-term use. Reductions in concentration of calcium in dialysate from 3.5 to 2.5 mEq/L have been shown to diminish the frequency of episodes of hypercalcemia in patients who are undergoing hemodialysis and are treated with calcium-containing, phosphate-binding agents (35,71). Further reductions, other than for very short intervals, are not recommended, however, in patients with adynamic renal osteodystrophy because of concerns about stimulating PTH secretion and parathyroid gland hyperplasia (72). The ionized calcium concentration in blood and the calcium level in dialysate are the key determinants of net calcium flux during hemodialysis (73). Net calcium transport is close to 0 when the dialysate calcium concentration is 2.5 mEq/L, which is equivalent to an ionized calcium level of 1.25 mmol/L. The blood ionized calcium concentration in most patients with ESRD falls within the range of 1.15 to 1.30 mmol/L. Lowering dialysate calcium levels to 2.0 mEq/L or less establishes an ionized calcium concentration in dialysate of 1.0 mmol/L or less. Such levels will substantially lower blood ionized calcium concentrations during dialysis and stimulate PTH secretion during each hemodialysis session in most patients whose predialysis ionized calcium levels are substantially higher. Thus, excess PTH secretion and parathyroid gland hyperplasia may be aggravated inadvertently by such an approach. Adynamic renal osteodystrophy that arises from bone aluminum deposition should be managed by discontinuing all aluminum-containing medications and by identifying other potential sources of aluminum exposure. For minimizing the risk of opportunistic infection during deferoxamine therapy, treatment with deferoxamine should be reserved for severely affected patients who have muscle pain and weakness and/or severe bone pain and fractures (11). However, Smith et al. (74) demonstrated high morbidity and mortality in those patients with both ESRD and positive surface stainable aluminum. More recently, specific criteria for the diagnosis and treatment of aluminum overload in patients with ESRD has been described (75). However, the current approach for the treatment of asymptomatic patients with aluminum overload remains to be defined. Indeed, the use of aluminum-free phosphate-binding agents alone may be sufficient to permit the slow resolution of aluminum-related bone disease in less severely affected patients (19,76). This work was supported in part by USPHS Grants DK-35423, DK-52095, and RR-00865 and funds from the Casey Lee Ball Foundation.