Parathyroid gland responsiveness to acute hypocalcemia in dialysis osteomalacia

Transcription

1 Kidney International, Vol. 23 (193), pp Parathyroid gland responsiveness to acute hypocalcemia in dialysis osteomalacia JEFFREY A. KRAUT, JAME H. HINABERGER, FREDERICK R. INGER, DONALD J. HERRARD, JOAN AXTON, JOEPH H. MILLER, KIYsHI KUROKAWA, and JACK W. COBURN The Medical and Research ervices, Veterans Administration Wadsworth Medical Center; Department of Medicine, University of California Los Angeles chool of Medicine, and the Department of Medicine, University of outhern California chool of Medicine, Los Angeles, California; and Medical and Research ervices, Veterans Administration Center, and the Department of Medicine, University of Washington chool of Medicine, eattle, Washington Parathyroid gland responsiveness to acute hypocalcemia in dialysis osteomalacia. The majority of chronic hemodialysis patients have elevated serum ipth levels and bone disease characterized by osteitis fibrosa. However, a small group of patients develop osteomalacic bone disease associated with normal or slightly elevated ipth values and a tendency to hypercalcemia which occurs either spontaneously or after treatment with small doses of vitamin D sterols. To examine the causes of the relatively low ipth levels, we evaluated the change in serum ipth levels that occurred in response to acute hypocalcemia, produced by dialysis using a low calcium dialysate, in II patients with osteomalacia and control hemodialysis patients. Dialysis against a dialysate free of calcium for 6 to 9 mm led to a fall in serum calcium to 7.5.2and mg/dl in the osteomalacic and control patients, respectively. erum ipth rose in controls from to pg/mi (P <.1), whereas in patients with osteomalacia it rose from 36 5 to pg/mi (P <.5), a value only slightly above normal for this PTH assay. These data suggest that the relatively low basal levels of serum ipth do not arise as a consequence of physiologic suppression of parathyroid gland function. This reduction in parathyroid function could contribute to the pathogenesis of low turnover osteomalacia. ensibilité de Ia glande parathyroidienne a l'hypocalcemie aiguë dans l'ostéomalacie de Ia dialyse. La majorité des malades en hemodialyse chronique ont une élévation des concentrations d'ipth sérique, et une ostéopathie caractérisée par une ostéite fibreuse. Cependant, un petit groupe de malades développe une atteinte osseuse osteomalacique associée a des valeurs d'ipth normales ou legerement dlevées et une tendance a l'hypercalcemie qui survient soit spontanément, soit apres traitment avec de petites doses de stérols vitaminiques D. Afin d'examiner les raisons de ces concentrations relativement basses d'ipth, nous avons étudié Ia modification des concentrations seriques d'ipth survenant en reponse a une hypocalcémie aigue produite par une dialyse avec un dialysat pauvre en calcium, chez 11 malades avec une ostéomalacie, et malades hcmodialyses controles. La dialyse contre un dialysat sans calcium pendant 6 a 9 mm a entrainé une chute de Ia calcémie a 7,5,2 et 7,2,2 mg/dl chez des malades ostéomalaciques et contrôles, respectivement. L'iPTH sérique s'est élevée chez les contrôles de a pg/mi (P <,1) tandis que chez les malades avec une ostéomalacie elle s'est élevée de 36 5 a pg/mi (P <,5), une valeur seulement légerement au-dessus de Ia normale avec ce dosage de PTH. Ces données suggerent que les concentrations de base relativement faibles d'ipth sérique ne sont pas La consequence d'une suppression physiologique du fonctionnement de Ia glande parathyroldienne. Cette reduction du fonctionnement parathyroidien pourrait contribuer a Ia pathogénie de l'ostéomalacie par renouvellement lent. The majority of patients maintained on long-term hemodialysis have elevated circulating levels of immunoreactive parathyroid hormone (ipth) and develop bone disease with histological features of osteitis fibrosa [1, 2]. However, a small fraction of dialysis patients develop osteomalacia which may be associated with hypercalcemia occurring either spontaneously or after treatment with small doses of vitamin D sterols [3 61. The serum immunoreactive parathyroid hormone levels in these patients are often only minimally elevated or even normal. This disorder has been termed "dialysis osteomalacia." The reason for the relatively low ipth levels and the possible pathogenic role for the low ipth levels in dialysis osteomalacia are presently unclear. Whether the low ipth levels are due to suppression of PTH secretion by the normal or slightly elevated levels of serum calcium or occurs as a result of an abnormality in parathyroid function is unknown. This study was designed to explore this question by examining the response of the parathyroid glands in patients with this syndrome to acute hypocalcemia, the most potent stimulus to parathyroid hormone secretion. The results indicate that patients with dialysis osteomalacia manifest a significantly smaller rise in parathyroid hormone secretion during acute hypocalcemia than do other dialysis patients. These observations suggest that the reduced basal levels of ipth in these patients reflect alterations in parathyroid function, which could occur due to differences in gland size or be secondary to altered cellular function. Further studies will be required to delineate the precise factors that alter parathyroid gland function in this disorder. Methods tudies were performed in II hemodialysis patients with osteomalacic bone disease and in eight control patients maintained on regular dialysis at the Veterans Administration Wadsworth Medical Center, Los Angeles, California. The former patients were all referred for evaluation of severe symptomatic bone disease, with recurrent fractures, bone pain, and disabil- Received for publication May 25, 192 and in revised form eptember 21, by the International ociety of Nephrology 725

2 726 Kraut et al Table 1. Clinical features and findings of bone biopsy Group Age, years Male/Female Duration of dialysis, years ubtotal PTX Bone histology OF Aplastic OM OM Dialysis osteomalacia 47 6/ " Control hemodialysis ity. All had clinical and biochemical features similar to those patients with "dialysis osteomalacia" previously reported [3]; several of the present patients had been included in that report. All demonstrated evidence of aluminum accumulation. The control hemodialysis patients were selected from the patients undergoing hemodialysis at the Veterans Administration Wadsworth Medical Center. They all lacked symptoms of musculoskeletal disease and a history of fractures; also, skeletal x-rays were normal in all but two, who had minimal features of subperiosteal resorption. Moreover, they had undergone hemodialysis in a center with effective water treatment and dialysate aluminum levels below 2..rg/liter and where de novo cases of "dialysis osteomalacia" have not been encountered. All studies were performed in the dialysis unit of Veterans Administration Wadsworth Medical Center. The protocol was approved by the Committee on Human Research, and informed consent was obtained from each participant before the study. The clinical features of the patients are summarized in Table I. The ages of 47 4 and 44 5 years in the patients with osteomalacia and the control dialysis patients, respectively, were not different. The osteomalacic group had a slight male predominance, whereas the control group consisted completely of males. The duration of hemodialysis prior to study ranged from 3 to 9 years (mean, 5.6 years) in patients with osteornalacia and from 3 months to 1 years (mean, 3.9 years) in the control dialysis patients. ubtotal parathyroidectomy had been performed 3 to 9 years prior to the study in seven of II osteomalacic patients whereas all the control hemodialysis patients had intact parathyroid glands. Iliac crest bone biopsies, performed in the 11 patients with dialysis osteomalacia, revealed isolated osteomalacia in eight, while three patients showed "patchy" osteomalacia; these patients showed no separation of double tetracycline labeling and have been classified as, "aplastic osteomalacia" [7, ]. Bone biopsies, available in three control patients, showed moderate osteitis fibrosa. Five patients with osteomalacia and two control patients were receiving l,25(oh)2d at a dose of.25 to.75 ig per day for treatment of their hone disease. One osteomalacic patient received 24,25(OH)2D 2.5 rg per day beginning 5 days before the study. All vitamin D sterols were held for 24 to 4 hr prior to study. None of the patients had liver disease, and all had daily urine volumes less than 2 ml. All patients were studied in the fasting state. Baseline plasma 3 44 / " Abbreviations: PTX, parathyroidectomy; OF, osteitis fibrosa; OM, osteomalacia Means EM. 3 samples were obtained for the determination of total and ionized calcium, phosphorus, magnesium, albumin, total protein, and immunoreactive parathyroid hormone. Hemodialysis was then initiated using calcium-free dialysate containing, in meq/liter: Na, 135; K, 2.; Cl, 12; and acetate, 35. Dialysis using a calcium-free dialysate was continued for 9 mm in all but two of the control and two of the osteomalacic patients. In these individuals the calcium-free dialysate was terminated at 6 mm because of symptoms of hypocalcemia. Calcium, 2.2 meq/liter, was then added to the dialysate and dialysis was continued for 12 to 15 mm. Blood was obtained from the arterial line of the dialyzer at intervals of 3 mm throughout the study for determination of total calcium, phosphorus, and ipth. Blood pressure was measured at intervals of 5 to 1 mm using a Dinamap (Crikiton Inc., Tampa, Florida). Body weight was recorded using an automatic bed scale. Dialyzers used included 1.36 m2 parallel plate (AB Gambro, Lund, weden) and hollow fiber, 1.2 m2 (Travenol Laboratories, Inc., Deerfield, Illinois). Analytical methods. Total calcium was determined by EGTA titration utilizing the Automatic Calcium Analyzer (Calcette, Precision cientific Group, Chicago, Illinois). Phosphorus was measured using the malachite green micromethod. Magnesium was determined using atomic absorption spectrometry. Ionized calcium was determined using a flow-through electrode (Orion Research, Cambridge, Massachusetts). Immunoreactive parathyroid hormone was determined by radioimmunoassay using methods described previously [9]. The antisera used was A211/41 (Burroughs Weilcome Laboratories, London, England); this antiserum is polyvalent but reacts primarily with the N-terminal of the PTH molecule. Normal values for this assay are below 5 pg/mi, and the lower limits for detection are 15 pg/mi. Aluminum content of bone was measured in a sample of trabecular bone from ten patients with osteomalacia using flameless atomic absorption spectrometry as described previously [1]. Results are expressed as mean I EM. Comparison of results between experimental periods and between groups were made using paired or unpaired tudent's t test and x2 analysis as necessary. Results Baseline serum biochemical values are shown in Table 2. Both total and ionized calcium were higher in the patients with osteomalacia than in controls, 1..4 compared to 9..2 mg/dl, and compared to mg/dl, respectively (P <.1). Four of the osteomalacic patients had serum calcium values greater than 1.5 ing/di, the upper limit of normal. erum magnesium was also slightly but significantly higher in osteomalacic patients, compared to mg/dl (P <.5). Immunoreactive PTH was increased markedly in control hemodialysis patients, pg/ml; whereas it was within the normal range in the osteomalacia patients, pg/mi. erum phosphorus concentrations were not significantly different in the two groups. Figure 1 depicts the effects of dialysis with a calcium-free dialysate followed by dialysate containing calcium, 2.2 meq- /liter, on serum calcium. Dialysis using a calcium-free dialysate for 9 mm led to a significant fall in mean total serum calcium to 7.5 and 7.3 mg/dl in the osteomalacic and control hemodialysis

3 Parathyroid gland responsiveness in dialysis osteomalacia 727 Osteomalacia Control hemodialysis Ca, mgldi ' P. mg/dl Mg, mg/dl 2.7.1" Alk P'tase, lu/liter ipth, pg/mi " a Means EM b Groups differ, P <.1. Table 2. Baseline biochemical featuresa I ( 4 4i E = U U U, 12 T 1 * T\\ 'bt T Time, minutes Fig. 1. erum calcium levels during dialysis using a low calcium dialysate in control hemodialysis (HD) patients (open circles) and patients with osteomalacia (closed circles). Data are means EM. The asterisk represents P <.5. patients, respectively. The subsequent addition of calcium, 2.2 meq/liter to the dialysate resulted in stabilization of total serum calcium at levels near mg/dl. Figure 2 depicts the change in ipth at 9 and 1 mm of study. By 9 mm, when serum calcium reached its nadir, control dialysis patients manifested a rise in serum ipth from to pg/mi (P <.1). By contrast, exposure of the osteomalacic patients to an identical degree of hypocalcemia resulted in only a small although significant, rise in ipth from to pg/mi (P <.5), a value just slightly above the normal level for this assay. By 1 mm, despite continuing hypocaicemia, ipth levels in both groups had decreased and were not significantly different from baseline. Moreover, as depicted in Figure 3, the increment in serum ipth at both 9 and 1 mm was lower in the osteomalacic patients than in controls. The osteomalacic patients were subdivided further into a group who had undergone parathyroidectomy and those with intact glands to examine whether prior parathyroidectomy may have affected the parathyroid gland responsiveness. As illustrated in Figure 2, all patients with intact glands manifested a rise in ipth greater than 1 pg/mi. In contrast, most patients who had undergone parathyroidectomy showed no change in Time, minutes Fig. 2. erum ipthlevels before and at 9 and 1 mm of hypocalcemic dialysis in control hemodialysis patients (left panel) and in patients with osteomalacia (right panel). Patients with osteomalacia are subdivided into those with intact glands (closed triangles) and those with an earlier history of subtotal parathyroidectomy (closed circles). Each symbol represents an individual patient. ipth at all, and only one person who had undergone parathyroidectomy showed an increase in ipth of more than 1 pg/mi. Thus, the fraction of osteomalacic patients having had parathyroidectomy who exhibited a rise in ipth greater than 1 pg/mi was lower than those with intact parathyroid glands, P <.5, by x2 analysis. However, the osteomalacic patients with intact parathyroid glands still manifested a smaller absolute rise in ipth at 9 mm than did control patients, and pg/ml, respectively (P <.5). Figure 4 depicts the relationship between individual values of ipth and total serum calcium for the osteomalacic and control patients. The levels of ipth were lower in the patients with osteomalacia than in control hemodialysis patients at all levels of serum calcium. The accumulation of aluminum in bone has been suggested as a pathogenic factor in osteomalacia [11]. Moreover, aluminum also accumulates in parathyroid glands 1121, and, theoretically, it could affect parathyroid gland function. If this were so, one might anticipate that individuals with the greatest aluminum burden might show more impairment of PTH secretion. Howe v- er, as illustrated in Figure 5, there was no relationship between changes in ipth levels and aluminum burden, as indicated by bone aluminum concentrations. Discussion The results of this study indicate that the relatively low serum ipth values observed in dialysis patients with osteomalacia arise due to alterations in parathyroid function and do not occur because of simple suppression by the prevailing level of blood calcium. This conclusion is based on the demonstration that dialysis-induced hypocalcemia elicited a significantly smaller rise in serum ipth levels in patients with osteomalacia than in "control hemodialysis" patients. Moreover, the larger increment in serum ipth occurred in the control hemodialysis patients despite the lower baseline serum calcium levels; indeed, the baseline serum calcium levels were below.5 mg/dl in three control patients, a level that is lower than that at which the greatest increment in PTH secretion might occur during

4 72 Kraut et al = F- E U, IF- (I) 2 12' 4. k A A Normal level A A* mm 1 mm Fig. 3. Changes in ipth (A) at 9 and 1 mm in osteomalacic patients (open bars) and control hemodialysis (HD) patients (cross-hatched bars). ymbols are: <.1; 'F <.5. acute hypocalcemia [131. By contrast, serum calcium fell from 1 to less than mg/dl in the osteomalacic patients, a range over which the sharpest increment in IPTH secretion might be expected. It could be argued that hypocalcemia of longer duration might be necessary to stimulate PTH secretion. The observation that serum ipth fell between 9 to 1 mm despite continued hypocalcemia in the control dialysis patients suggests that PTH is secreted rapidly in response to hypocalcemia in the secondary hyperparathyroidism of uremia. tudies in nonuremic animals also suggest that PTH secretion occurs rapidly but is not sustained despite persistent hypocalcemia [14]. Thus, it seems unlikely that a longer duration of hypocalcemia would have elicited any greater increment in serum ipth in the patients with osteomalacia. A comment regarding our interpretation of the changes in serum ipth levels is due. The absolute increment in ipth was lower in the osteomalacia patients; however, the percent increase in serum ipth in the groups was similar, approximately 4% in both. The msjority of ipth values in the osteomalacia patients were near the lower limits of detection for this assay; thus, there is less confidence in the small changes in ipth noted. It is for this reason that we believe that comparison of the absolute change in ipth is more meaningful than the percentage increase. Unfortunately, the response of normal humans, who have baseline ipth levels similar to the osteomalacia patients to the hypocalcemic stress, was not evaluated in this study. In previous studies of normal subjects, serum ipth rose by at least fourfold above control values in response to hypocalcemia induced by the infusion of EDTA [15]; thus the attenuated response in the osteomalacia patients is even more striking. Furthermore, it could be argued that a proportionally greater increase in serum ipth might be expected, if the lower baseline ipth levels in the osteomalacia patients occurred due to suppression by hypercalcemia. Approximately 6% of the patients with osteomalacia had erum calcium, mg/d/ Fig. 4. Relationship between individual values of serum ipth and serum calcium in control hemodialysis patients (open circles) in patients with osteomalacia and intact parathyroid glands (closed trian gles) and those with osteomalacia and a history of subtotal parathyroidectomy (closed circles) during hvpocalcemic dialysis. The two interrupted lines denote the upper limits of normal and lower limits of detection, respectively, for the PT H assay. undergone prior subtotal parathyroid resection: indeed, these patients did show a smaller increment in serum ipth than did the osetomalacia patients without prior parathyroid surgery. However, there was no evidence of surgical total hypoparathyroidism in any of these patients, as evidenced by prolonged hypocalcemia or a need for vitamin D therapy to maintain a normal serum calcium. Thus, there was little evidence for total parathyroid removal in these patients although the surgical reduction in gland mass may have contributed to the reduced response. These studies do not provide evidence regarding the cause of the reduced release of PTH in response to hypocalcemia. The differences in PTH secretion in response to hypocalcemia could arise due to differences in gland size, due to an intrinsic change in the parathyroid cells, that is, a shift in the "set point" or the calcium levels at which the PTH secretion by the cell is altered [16], or a combination of both factors. The present observations do not allow us to differentiate between these possibilities. Although several of the osteomalacic patients had received vitamin D sterols for treatment of bone disease prior to study, there was no difference in the response to hypocalcemia in those who received vitamin D compared to those who did not. Recently a high level of aluminum was shown to occur in the bones of uremic patients with osteomalacia [17]. Also, a possible pathogenic role for aluminum accumulation has been proposed [1, 19]. tudies of parathyroid glands obtained from hyperparathyroid and normal humans and from rats also showed preferential accumulation of aluminum in parathyroid glands [12]. Furthermore, a recent in vitro study demonstrated that high concentrations of aluminum can inhibit PTH secretion in cell culture [2]. Thus, it is conceivable that aluminum accumulation impairs parathyroid hormone secretion.

5 .. Parathyroid gland responsiveness in dialysis osteomalacia 729 National Institutes of Health grant AM1475 and contract AM5221 and by Veteran Administration Research funds. The authors thank Dr. K. Gerzi for technical assistance and the nurses and technicians of the Dialysis Unit in the performance of this study, and Ms. L. Reed and Mrs. B. Bales for their skill in the preparation of this manuscript II- - E Cl, < Bone aluminum, mg/kg dry weight Fig. 5. Relationship between bone aluminum Content and the maximal rise in serum ipth in patients with osteomalacia. Each closed circle represents a separate patient. In this study, no relationship between changes in PTH secretion and aluminum content of bone could be demonstrated. It is possible that bone aluminum content may not reflect the aluminum content of the parathyroid glands. Moreover, a majority of these patients had undergone parathyroidectomy, and, therefore, it may be difficult to distinguish the independent effects of subtotal parathyroidectomy from a possible effect of aluminum on PTH secretion. Finally, there is the question of the role of the relatively low basal and stimulated ipth levels in the pathogenesis of the bone disease. The occurrence of a similar bone disease in some uremic patients following parathyroidectomy [21, 22] and our observations of reduced parathyroid hormone secretion in these patients are consistent with a role for impaired parathyroid hormone function in the genesis of this bone disease. Mild osteomalacia has been reported in patients with hypoparathyroidism [23], although no impairment in bone mineralization has been noted in surgically thyroparathyroidectomized dogs with reduced renal function which were followed for more than a year [24]. Therefore, it is unclear whether the absence of parathyroid hormone alone is sufficient to cause osteomalacia. The reduced PTH activity will lead to low turnover of bone, and this could allow greater accumulation of aluminum in bone and perhaps contribute to the toxicity of aluminum. It is also possible that low PTH levels may favor the localization of aluminum along the mineralization front [25], where it might be more capable of inhibiting the mineralization of bone. Further studies are required to determine the possible synergism between low ipth activity and the accumulation of aluminum in the pathogenesis of osteomalacia. Acknowledgments A preliminary report of this work was presented at the meeting of the Western ection of the American Federation for Clinical Research, Carmel, California, February 6, 191, and published in abstract form in C/in Res 29:12A, 191. Portions of this study were supported by Reprint requests to Dr. J. W. 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