Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia

Kidney International, Vol. 24 (1983), pp. 364—370

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia DENNIS ANDRESS, ARNOLD J. FELSENFELD, ANNE VoloTs, and FINcIsco LLACH The Department of Medicine, University of Oklahoma Health Sciences Center and the Veterans Administration Medical Center, Oklahoma City, Oklahoma

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia. The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and

compared to those with osteitis flbrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal 0.33 vs. 0.87 0.53 parathyroid hormone response (± SD) (0.39 ng/ml, P < 0.05) and maximum carboxy terminal parathyroid hormone response (± SD) (0.36 0.20 vs. 0.84 0.47, P < 0.02) to hypocalce-

the only bone lesion [2—4]. The incidence of "pure" osteomala-

cia appears to have a geographic distribution that has been closely linked to the aluminum content of the dialysate [5, 6].

Patients with 'pure" osteomalacia are often characterized clinically by disabling musculoskeletal pain and spontaneous, nontraumatic skeletal fractures [4, 6]. Biochemical features include a relative deficiency of parathyroid hormone (PTH), a mia. The decline in plasma calcium was greater in patients with tendency toward hypercalcemia, especially after therapy with vitamin D metabolites, and a normal or only minimal elevation osteomalaciaat 90(P <0.05), l20(P <0.01), and 150 min(P <0.01). In osteomalacia patients the surface density of histologically detectable of serum alkaline phosphatase [7]. trabecular bone aluminum correlated directly with the percent relative Recent studies have implicated aluminum in the genesis of osteoid volume (P < 0.005) and inversely with the maximum amino this syndrome. Aluminum deposits at the interface of osteoid terminal parathyroid hormone response to hypocalcemia (P < 0.025). These results suggest that hemodialysis patients with osteomalacia have and mineralized bone have been documented both by electron diminished secretion of parathyroid hormone and a decreased ability to microprobe analysis [8] and histologic techniques [9]. Some restore plasma calcium homeostasis during hypocalcemia. evidence has also accumulated suggesting that the inappropriately low circulating PTH levels in these patients may also Réponse de l'hormone parathyroidienne a l'hypocalcemie chez des malades hémodialyses atteints d'ostéomalacie. La réponse de l'hormone contribute to the production of osteomalacia [7, 10]. In addiparathyroldienne a l'hypocalcémie a été étudiée chez des malades tion, recent data show parathyroid gland dysfunction, as exhibhémodialyses atteints d'ostéomalacie et comparée a Ia réponse de ceux ited by a markedly diminished PTH response to hypocalcemia atteints d' osteIte fibreuse. L'hypocalcémie était induite pendant l'hé[11]. A possible association between aluminum toxicity and modialyse en utilisant un dialysat dépourvu de calcium. Les malades altered parathyroid gland function is suggested by the observaatteints d' ostéomalacie avaient une diminution de Ia réponse maximale 0.33 tion that aluminum may diminish PTH secretion [121; furtherde l'hormone parathyroIdienne amino-terminale (± SD) (0.39 contre 0.87 0.53 ng/ml, P < 0.05) Ct de Ia reponse maximale de more, PTH may facilitate aluminum deposition in bone [81. 0.20 l'hormone parathyroldienne carboxy-terminale (± SD) (0.36 In the present study, PTH secretion was evaluated during contre 0.84 0.47, P < 0.02) a l'hypocalcemie. La diminution de Ia acute hypocalcemia in hemodialysis patients with osteomalacia. calcémie était plus forte chez les malades atteints d'ostéomalacie a 90 At the time these patients were studied, three had characteristic (P < 0.05), 120 (P < 0.01) et 150 mm (P < 0.01). Chez les malades ostéomalaciques Ia densité de surface de l'aluminium de l'os trabécu- features including diffuse musculoskeletal pain and nontraumatlaire histologiquement detectable était directement corrClée avec le ic fractures, two patients had minimal musculoskeletal compourcentage relatif de volume ostCoIde (P < 0.005) Ct inversement avec plaints and no fractures, and three patients were completely Ia reponse maximum de l'hormone parathyroIdienne amino-terminale a l'hypocalcémie (P < 0.025). Ces résultats suggèrent que les malades asymptomatic. The latter five patients were discovered to have hémodialyses atteints d' ostéomalacie ont une diminution de Ia sécré- pure osteomalacia because iliac crest biopsies are performed tion de l'hormone parathyroIdienne et une diminution de Ia capacité de routinely in our dialysis population. The present study evalurestaurer l'homCostasie de Ia calcémie pendant une hypocalcCmie. ates the PTH response to hypocalcemia and determines the correlation between PTH responsiveness and bone aluminum deposition. Chronic renal failure patients receiving maintenance dialysis will almost uniformly demonstrate renal osteodystrophy when Methods bone histology is obtained [1, 21. Although osteitis fibrosa is the a number of patients have predominant histological form [31, Twenty-six patients, eight with histologically documented osteomalacia, either in combination with osteitis fibrosa or as osteomalacia and 18 with osteitis fibrosa, receiving maintenance hemodialysis were studied. All were routinely dialyzed three times each week with a dialysate calcium bath of 3.0 or 3.5 mEq/liter. The water for the dialysate was treated with either Received for publication September 14, 1982 reverse osmosis (24 patients) or de-ionization (2 patients). All and in revised form February 8, 1983 patients received oral aluminum-containing antacids in an at© 1983 by the International Society of Nephrology tempt to maintain predialysis serum phosphate at 4.5 to 5.5 364

PTH response to hypocalcemia in dialysis osteo,nalacia

365

Results Pertinent clinical and biochemical data for the patients with

mg/dl. The mean duration of dialysis was 66.6 41 months SD), range 19 to 110 months, for the osteomalacia (mean patients and 33.4 28 months, range 4 to 79 months, for patients and osteitis fibrosa. At the time of study no patient was receiving any vitamin D, cimetidine, or propranolol. There were five males and three females in the osteomalacia group,

osteomalacia and osteitis fibrosa are presented in Table 1.

and 16 males and two females in the group with osteitis fibrosa. Three osteomalacia patients and one osteitis fibrosa patient had a previous parathyroidectomy.

in the osteomalacia group (P < 0.02), the duration of dialysis longer in osteomalacia patients (P < 0.025), and serum alkaline phosphatase greater in the osteitis fibrosa group (P <0.03).

Anterior iliac crest bone biopsies were performed and analyzed prior to the study in all patients. A Mayo or a Bordier biopsy needle was utilized for the biopsies. The Mayo needle has an internal diameter of 7.5 mm and the Bordier 6 mm. Quantitative histomorphometric analysis of undecalcified 5 i Goldner stained sections was accomplished with a Merz-

There were no differences between the two groups with respect to age, baseline plasma calcium, C-PTH, and magnesium and serum phosphorus levels. The basal plasma N-PTH was lower

Mean values of bone histologic parameters for each group are shown in Table 2. Osteoblastic osteoid (P < 0.001), osteoclastic

resorption (P < 0.001), total resorption (P < 0.001), osteo-

clasts/mm2 (P < 0.005), and endosteal fibrosis (P < 0.02) were greater in osteitis fibrosa. Total surface osteold (P < 0.025) was greater in osteomalacia. Schenk reticle [13]. Patients were classified as having osteomaSerial calcium decrements during zero calcium dialysis, mealacia on the basis of a marked reduction or cessation of bone sured as the change from baseline (mg/dl), are shown in Figure formation as determined by double tetracycline labeling. Addi- 1. Although significant differences between the groups are not tional features considered included the virtual absence of both definitely established during the first 60 mm, subsequently the osteoblastic osteoid and endosteal fibrosis. Osteitis fibrosa was osteomalacia patients have a more rapid decline in plasma determined by the presence of cellular activity (both osteoblasts calcium. At 90 (P < 0.05), 120 (P < 0.01), and ISO mm (P < and osteoclasts), endosteal fibrosis, and active bone formation 0.01), significant differences are observed between the osteoas determined by double tetracycline labeling. malacia and osteitis fibrosa patients. Bone aluminum stains were performed on the undecalcified The maximum N-PTH response (0.39 0.33 vs. 0.87 0.53 sections according to the method described by Maloney et al ng/ml, P < 0.05) and the maximum C-PTH response (0.36 [91. The trabecular surface density of aluminum was obtained 0.20 vs. 0.84 0.47 nglml, P < 0.02) to hypocalcemia were

by counting the trabecular aluminum deposits with a Merz- markedly reduced in osteomalacia as compared to osteitis Schenk reticle [13]. Surface aluminum was counted without fibrosa. As shown in Figure 2, a comparison of the two groups knowledge of changes in PTH. revealed that the change in N-PTH concentration was signifiAll patients were dialyzed against a zero calcium dialysate to

cantly higher in osteitis fibrosa patients at 30 (P <0.01), 60(P <

induce hypocalcemia. Plasma calcium was determined by 0.05), 90 (P < 0.02), and 120 mm (P < 0.05). Differences in CEGTA titration utilizing an automated calcium analyzer (Cal- PTH were observed at 30 (P < 0.025), 60 (P <0.02), 90 (P < cette, Precision Systems Inc., Sudbury, Massachusetts). Para- 0.005) and 120 mm (P < 0.01). thyroid hormone, both amino (N) and carboxy (C) terminal Among the osteomalacia group the comparison of the basal fragments, were determined according to a previously de- N-PTH concentration to concentrations at subsequent time scribed method [14]. Normal plasma levels are 0.05 to 0.5 ng/ml intervals revealed a minimal, but significant increase only at 30 for the carboxy terminal and 0.05 to 0.4 ng/ml for the amino mm (P < 0.05). The same comparison with C-PTH revealed terminal fragment, Plasma magnesium was determined by minimal, but significant increases at 30 and 60 mm (P < 0.02). atomic absorption spectrophotometry. Serum phosphorus and Among the osteitis fibrosa patients, both N-PTH and C-PTH alkaline phosphatase were measured by standard laboratory concentrations increased significantly from basal values at all determinations with a multichannel autoanalyzer (Technicon, subsequent time intervals (P < 0.01). Ardsley, New York). Measurements of plasma calcium and Three osteomalacia patients and one osteitis fibrosa patient PTH in osteomalacia patients were obtained at baseline, 15, 30, underwent a previous parathyroidectomy. In the osteomalacia 45, and 60 mm, and every 30 mm thereafter. Similar measure- patients with parathyroidectomy, the basal N-PTH levels were ments were performed in the patients with osteitis fibrosa 0.05, 0.05, and 0.33 nglml. During hypocalcemia, the maximum except that sampling was not obtained at 15 and 45 mm after N-PTH increases were 0.39, 0.06, and 0.19 ng/ml, respectively. initiation of zero calcium dialysis. Data obtained at IS and 45 Their basal C-PTH levels were 1.54, 0.78, and 1.04 ngiml. mm in the osteomalacia patients were not utilized for compari- During hypocalcemia, the maximum C-PTH increases were son of the two groups but were included to determine maximum 0.45, 0.24, and 0.38 nglml, respectively. Thus, these individuals N-PTH response in Figure 3. Criteria for cessation of the zero were capable of mild increases of both N-PTH and C-PTH, calcium dialysis included a dialysis period of at least 150 mm which, in general, were not different from other group memunless symptoms of hypocalcemia developed. If patients were bers. The one osteitis fibrosa patient with a prior parathyroidec. asymptomatic, the study was continued until the plasma calci- tomy had basal N-PTH and C-PTH levels of 0.37 and 0.73 um reached a nadir of at least 7.0 mg/dl. nglml. During hypocalcemia, the maximum N-PTH and C-PTH Statistics. Statistical analyses were performed with the Stu- levels increased by 1.09 and 1.06 nglml, respectively. dent t test, linear regression analysis, and the Wilcoxson Rank Among the osteomalacia patients, a spectrum of N-PTH and Sum Test (WRST). The WRST was only used for the compari- C-PTH responsiveness to hypocalcemia was found. Four pason of serum alkaline phosphatase in Table 1. All results are tients had less than a 0.2 ng/ml increase in N-PTH while two expressed as the mean value SD, except the figures which are patients had greater than 0.6 nglml increment. Among the 18 mean value SE. osteitis fibrosa patients, 12 had greater than a 0.6 ng/ml increase

366

Andress et a!

Table 1. Baseline clinical and biochemical data for osteomalacia and osteitis fibrosa patients Plasma

Serum

.

Amino

Duration of dialysis

Osteomalacia Mean SD

Osteitis fibrosa Mean ± SD

P value Normal values

ng/ml

Carboxy parathyroid hormone nglml

0.15 ±0.14

1.29

2.7

6.1

101

±1.3

±0.52

±1.3

±1.3

±63

9.4 ±0.64 NS 8.5 to 10.5

0.53 ±0.40 <0.02 0.05 to 0.5

±0.54 NS 0.05 to 0.5

6.6 ±2.3 NS 2.5 to 4.5

203 ±206 <0.03 30 to 115

mgld!

ng/ml

ag/rn!

mg/d!

U/liter

Age

months

Calcium mg/dl

53

67 ±41

±14 54 ±11 NS

9.8

33

±28 <0.025

parathyroid hormone

Magnesium mEqiliser

mg/dl

2.20

1.50

Alkaline phosphatase U/liter

Phosphorus

±0.22 NS 1.5 to 1.9 mEqiliter

Table 2. A comparison of bone histology Osteitis fibrosa

Osteomalacia

Mean ± so

0.13 ± 0.3

Osteoblastic osteoid, % Total osteoid, % Osteoclastic resorption, % Total resorption, % Osteoclasts/mm2 Absolute osteoid volume, % Relative osteoid volume, % Bone volume, % Fibrosis volume, %

Range

0 to 0.7 0.7 to 8.4 0 to 1.0 1.3 to 10.2

± 8.3

13 to 36 10 to 28.3

18

0.06 ± 0.07

Range

P value

10.4 ± 7.1

4.2 to 33.9 8.0 to 82 2.8 to 19.2 5.6 to 27.3 1.0 to 9.0 0.3 to 10.4 2.0 to 47 7.2 to 30.3 0.5 to 17.9

<0.001 <0.025 <0.001 <0.001 <0.005 NS NS NS

63 ± 18

80 ± 13 1.3 ± 1.8 2.9 ± 1.0 0.6 ± 0.7 4.7 ± 3.6

24 ± 8.1

Mean ± so

60 to 95 0 to 5.2

8.9 ± 4.5

0 to 0.2

13.1 ± 6.3

3.3 ± 2.3 3.1 ± 2.6 16 ± 12

20 ± 7.2 4.0 ± 4.2

•

<0.02

in N-PTH, and none had an increment less than a 0.2 ng/ml. With respect to C-PTH four osteomalacia patients had less than

tients. Nonetheless compared to patients with osteitis fibrosa, the osteomalacia group had a diminished N-PTH and C-PTH

a 0.3 nglml increase, while only one patient with osteitis fibrosa failed to increase C-PTH by 0.3 nglml. At the nadir of plasma calcium, the N-PTH level was less than the maximum response in six osteomalacia patients and 16 osteitis fibrosa patients. At

response to hypocalcemia. This suggests that, as a group, osteomalacia patients are unable to appropriately increase PTH levels.

The peak values for PTH in osteomalacia often occurred the nadir of plasma calcium, the C-PTH level was less than during the first 60 mm of hypocalcemic dialysis, and not with maximum response in four osteomalacia patients and 14 pa- the nadir of plasma calcium. Among the osteomalacia group, maximum N-PTH levels were observed in four individuals and tients with osteitis fibrosa. An inverse correlation was found between the surface density maximum C-PTH levels in five individuals during the first 60 of trabecular bone aluminum versus the maximum N-PTH mm of hypocalcemic dialysis. Although in general the magniresponse to hypocalcemia (Fig. 3, P < 0.025). The surface tude of N-PTH and C-PTH response was small, nonetheless a density of trabecular bone aluminum also correlated with the solitary measurement at 90 mm as reported by Kraut et al [11] percentage of relative osteoid volume (Fig. 4, P < 0.005), and would have failed to demonstrate the maximum N-PTH and Cboth the density (r = 0.86, P < 0.005) and percent (r = 0.85, P < PTH level in all eight patients. If the 90-mm PTH value is recorded as a percentage of the maximum value, N-PTH is only 0.001) total surface osteoid.

31% and C-PTH 36 27% of the maximum value. Thus, a solitary 90-mm value may not reflect maximum PTH secretion. Dialysis osteomalacia is characterized by relatively low lev- Nonetheless, because the magnitude of PTH increase is often els of PTH and a tendency toward hypercalcemia [7]. Whether small, a solitary 90-mm PTH value is probably representative of the hypercalcemia is responsible for the low levels of PTH, or impaired PTH secretion.

29

Discussion

parathyroid gland dysfunction exists in these patients, is unclear. Results from Kraut et al [11] suggest that osteomalacia

The possibility exists that the difference in duration of maintenance dialysis therapy between groups may have affect-

patients fail to appropriately increase N-PTH despite a hypocalcemic stimulus. Our results support the contention that abnormal parathyroid gland function does exist among some dialysis

ed PTH secretion. To test this possibility, from the osteitis

osteomalacia patients. However, considerable variability in P1'H responsiveness was observed among osteomalacia pa-

duration of dialysis, 68

fibrosa group we selected the only six patients who had received hemodialysis for more than 50 months. Their mean 7 months, was similar to the osteomalacia group and their maximum N-PTH and C-PTH response

PTH response to hypocalcemia in dialysis osteomalacia

367

bates the severity of osteomalacia [16, 171. In addition to skeletal deposition, increased aluminum content has been documented in several organs including liver and spleen [18]. The

finding of increased aluminum content in parathyroid glands suggests the possibility of altered parathyroid gland function [19]. Morrisey et al, utilizing parathyroid gland cell cultures, observed that aluminum inhibited PTH secretion [12]. Whether this finding represents a specific effect of aluminum on PTH secretion, or is a nonspecific phenomenon of heavy metals remains to be determined [201. Because of the association between aluminum toxicity and dialysis osteomalacia, and possibly between aluminum and altered parathyroid gland function, a comparison of bone aluminum and PTH responsiveness was made. Such a comparison assumes that bone aluminum reflects the total body aluminum burden including the parathyroid glands and that the method for the detection of bone aluminum is accurate. Alfrey, Hegg, and Carswell [18] have shown that the aluminum content of various tissues increase in uremic individuals; however, analysis of

E

E

0 U (0 U (0

E

(0

0

the parathyroid glands for aluminum content was not performed. A histologic technique for bone aluminum deposits demonstrated a significant correlation with the bone aluminum content determined by atomic absorption [9]. With this technique, we observed a significant correlation between the surface density of trabecular bone aluminum and N-PTH responsiveness to hypocalcemia. This finding suggests that the bone

aluminum burden may reflect the aluminum content of the parathyroid gland which in turn may affect PTH secretion. The possibility also exists that parathyroid gland dysfunction is a separate component of the dialysis osteomalacia syndrome and

varies in the same direction but independent of aluminum Time, minutes

Fig. 1. The decrease in plasma calcium during zero calcium dialysis. The group (N = 8) with osteomalacia (0) is compared to the group (N = 18)

with osteitis fibrosa (•). The decrease in plasma calcium was

significantly greater with osteomalacia at 90, 120, and 150 mm. * O < 0.05;

** < 0.01.

burden. As shown in Figure 4, the significant correlation between the relative osteoid volume and trabecular bone aluminum surface

density, corroborates the results of Hodsman et al [21] who reported direct correlation of bone aluminum in osteomalacia, and trabecular osteoid. A similar finding has been reported by Cournot-Witmer et al [22]. The observed low baseline PTH levels and the failure of PTH to respond appropriately to hypocalcemia may contribute to the

0.41 nglml, respectively. These genesis of osteomalacia. This hypothesis is supported by the was 0.90 0.35 and 0.83 values are much higher than those observed in the osteomalacia reported conversion of osteitis fibrosa to osteomalacia followgroup. Thus, it is unlikely that the duration of dialysis affected ing parathyroidectomy [101. In addition, preliminary data by Malluche et al [23] in azotemic dogs have suggested that PTH PTH secretion. Another consideration is whether or not the inclusion of may be required for 1,25 dihydroxycholecalciferal to have a patients with prior parathyroidectomy may have altered the positive effect on bone formation. Of interest in our osteomalacia patients was the variable results. Of the three individuals in the osteomalacia group, one had the second highest basal N-PTH level in the group, and response to hypocalcemia. Even with uniformly low basal Nanother responded to hypocalcemia by increasing the N-PTH PTH levels, most osteomalacia patients were incapable of an and C-PTH level by 0.39 and 0.45 nglml, respectively. The only appropriate N-PTH response to hypocalcemia, but two patients parathyroidectomized patient in the osteitis fibrosa group re- did have a significant and sustained PTH response. These sponded to hypocalcemia by a marked increase in PTH levels. findings suggest that impaired PTH release is not required for Thus, separate analysis suggests that PTH response of parathy- the development of dialysis osteomalacia and bone aluminum roidectomized patients was not different from the other accumulation. However, in general, the patients with less total surface osteoid had a more pronounced N-PTH response (r = patients. Aluminum has been implicated both by epidemiological and 0.71, P < 0.05). The highest frequency of dialysis osteomalacia has occurred experimental evidence as a causal agent in the production of dialysis osteomalacia [5, 6]. Ellis, McCarthy, and Herrington in areas of high aluminum concentration and may be related to [15] demonstrated that intraperitoneal aluminum injections in the absence of appropriate water purification systems [5, 6, 24— rats will produce osteomalacia. Subsequent studies in rats have 26]. In six of our osteomalacia patients, reverse osmosis was shown that the presence of chronic renal failure greatly exacer- utilized for water purification. In the other two patients, de-

368

Andress A

et al B

0.8-

0.6 a)

C

0 E

0

-C

0

>

-c

0.4

0

0. a) C

E a)

0 C

0.2

E

60

120

150

30

Time, minutes

60

90

120

150

Time, minutes

Fig. 2. A comparison of PTH response to hypocalcemia in osteomalacia (0) and osteitisfibrosa (I). A The amino terminal PTH response was significantly greater at 30, 60, 90, and 120 mm in osteitis fibrosa. B The carboxy terminal PTH response was significantly greater at 30, 60, 90, and 120 mm in osteitis fibrosa. * P < 0.05; ** P < 0.01.

ionization was used. In addition, we observed osteornalacia

prevent calcium exchange; and (5) finally, the blunted PTH

with stainable aluminum in additional hemodialysis patients in whom reverse osmosis systems were utilized. Thus, it would appear that aluminum transfer may come from sources other than dialysate water [27, 28]. As shown in Figure 1, the ability of the osteomalacia patients to maintain their plasma calcium during zero calcium dialysis was compromised. Since the patients were not receiving calcium orally, via the dialysate, and renal excretion was insignifi-

response in osteomalacia may prevent effective calcium

cant, it is likely that the principal source of calcium for the

reclamation.

It is our impression that osteomalacia is a multifactorial entity. Thus, at one end of the spectrum are patients with abundant trabecular bone aluminum deposits and a failure to appropriately increase N-PTH with hypocalcemia; at the opposite end are patients with minimal trabecular bone aluminum deposits and an appropriate N-PTH response to hypocalcemia. For the most part, the latter patients have a milder form of

maintenance of plasma calcium during zero calcium dialysis is the skeleton. Several possible explanations exist for the failure of osteomalacia patients during hypocalcemia to reclaim skeletal calcium as effectively as patients with osteitis fibrosa: (I)

osteomalacia. It is possible that in the milder group, the

The presence of surface osteoid may act as a reservoir for

genesis of the mild osteomalacia. In summary, a zero calcium dialysis was performed to induce hypocalcemia in eight dialysis patients with osteomalacia and 18 dialysis patients with osteitis fibrosa. In the osteomalacia patients, a diminished N-PTH and C-PTH response to hypocalcemia was observed. They had a more precipitous decline in plasma calcium during the zero calcium dialysis. The surface density of trabecular bone aluminum correlated with both the maximum N-PTH response to hypocalcemia and the percentage of relative osteoid volume. In conclusion, dialysis patients with

calcium [29] or prevent osteoclast access to mineralized bone surface [29]; (2) the decreased number of osteoclasts/mm2 may be incapable of augmenting bone resorption. Furthermore, during a short time period recruitment of new osteoclasts is not possible, while activation of existing osteoclasts may require only 15 to 30 mm [30]; (3) if "osteocytic osteolysis" (resorption of bone by osteocytes) actually occurs, a difference between osteitis fibrosa and osteomalacia is possible [31]; (4) aluminum located on the bone surface may act as a physical barrier to

aluminum and low basal N-PTH levels may contribute to the development of osteomalacia. Other factors besides aluminum

and a relative PTH deficiency may also contribute to the

369

PTH response to hypocalcemia in dialysis osteomalacia

E

4500-I

E

4000

>-

3500 -'

4500 4000

N=8

N=8

= —0.70 P < 0.025

CO

C

3500

5) 5)

3000

-

2500

-

C.) CO

CO

r= 0.86 P< 0.005

3000

E

C 2000

2500

E 1500

CO

2000-

CO

C 0 .0 1000 CO

1500

C.)

5)

.0CO I—

500 0 0.1

0:2

0:3

0.4

0.5 0.6

0.7

0.8

0:9

to

Maximal N-PTH change, ng/mI

500

Fig. 3. The maximum amino terminal PTH (N-PTH) change compared

to irabecular bone aluminum surface density in the patients with osteomalacia.

0 10

20

30

40

Related osteoid volume, %

Fig. 4. A comparison of the relative osteoid volume (%) with the

osteomalacia have a blunted PTH response to hypocalcemia when compared to patients with osteitis fibrosa. The presence of aluminum may be an important factor in the PTH response. Acknowledgments A preliminary report of this work was presented at the 4th Annual Meeting of the American Society for Bone and Mineral Research, San Francisco, California, June 13—15, 1982, and the 15th Annual Meeting of the American Society of Nephrology, Chicago, Illinois, December

12—14, 1982. It was published in abstract form in Calcif Tissue mt 34:S37, 1982, and Kidney mt 23:94, 1983. This work was, in part, supported by a Research Advisory Group grant from the Veterans Administration. The authors thank Mrs. W. Savage and Mrs. C. Clay for preparation of the manuscript, and Mr. C. Haygood and Mr. P. Wilson for technical assistance. Reprint requests to Dr. A. J. Felsenfeld, Nephrology Section (1 / JO), Veterans Administration Medical Center, 921 N.E. 13th Street, Oklahoma City, Oklahoma 73104, USA

Reference 1. RITZ E, KREMPIEN B, MEHLS 0, MALLUCHE H: Skeletal abnormal-

ities in chronic renal insufficiency before and during maintenance hemodialysis. Kidney mt 4:116—127, 1973 2. SHERRARD DJ, BAYLINK Di, WERGEDAL JE, MALONEY NA:

Quantitative histological studies on the pathogenesis of uremic

bone disease. J Clin Endocrinol Metab 39:119—135, 1974 3. ELLIS HA, PEART KM: Azotemic osteodystrophy: Quantitative study on iliac bone. J Clin Pathol 26:83—101, 1973 4. ALVAREZ-UDE F, FEEST TO, WARD MK, PIERIDE5 AK, ELLIS HA, PEART KM, SIMPSON W, WEIGHTMAN D, KERR DNS: Hemodialy-

sis bone disease: Correlation between clinical, histologic, and other findings. Kidney mt 14:68—73, 1978 5. WARD MD, FEEST TG, ELLIS HA, PARKINSON IS, KERR DNS, HERRINGTON J, GOODE GL: Osteomalacia dialysis osteodystrophy.

Evidence for a water-borne aetiological agent, probably aluminum. Lancet 1:841—845, 1978 6. PIERIDES AM, EDWARDS WG JR, CULLUM UX JR, MCCALL JT, ELLIS

HA: Hemodialysis encephalopathy with osteomalacia frac-

tures and muscle weakness. Kidney mt 18:115—124, 1980

trabecular bone aluminum surface density in patients

wit/i

osteomalacia.

7. HODSMAN AB, SHERRARD Di, WONG EGC, BRICKMAN AS, LEE DB, ALFREY AC, SINGER FR, NORMAN AW, COBURN JW: Vitamin

D resistant osteomalacia in hemodialysis patients lacking secondary hyperparathyroidism. Ann Intern Med 94:629—637, 1981 8. COURNOT-WITMER 0, ZINGRAFF J, PLACHOT ii, ESCAIG F, LEFEVRE R, BOUMATI P. BOURDEAU A, GARABEDIAN M, GALLE P. BOURDON R, DRUEKE T, BALSAN 5: Aluminum localization in bone

from hemodialyzed patients: Relationship to matrix mineralization. Kidney mt 20:375—385, 1981 9. MALONEY NA, OTT SM, ALFREY AC, MILLER NL, COBURN JW, SHERRARD Di:

Histological quantitation of aluminum in iliac bone from patients with renal failure. J Lab Clin Med 99:206—2 16. (982 10. FELSENFELD AJ, HARRELSON JM, GUTMAN RA, WELLS SA, DREZNER MK: Osteomalacia after parathyroidectomy in patients with uremia. Ann Intern Med 96:34—39, 1982 11. KRAUT iA, SHINABERGER JH, SINGER FR, SHERRARD DJ, SAXTON

J, MILLER JH, KUROKAWA K, COBURN JW: Parathyroid gland responsiveness to acute hypocalcemia in dialysis osteomalacia. Kidney mt 23:725—730, 1983 12. M0RRI55EY J, ROTHSTEIN M, MAYOR G, SLATOPOLSKY E: Sup-

pression of parathyroid hormone secretion by aluminum. Kidney mt 23:699—704, 1983 13. MERZ WA, SCHENK RK: Quantitative structural analysis of human cancellous bone. Acta Anat (Base!) 75:54—66, 1970 14. LLACH F, FELSENFELD AJ, HAUSSLER MR: The pathophysiology

of altered calcium metabolism in rhabdomyolysis-induced acute renal failure. N EngI J Med 305:117—123, 1981 15. ELLIS HA, MCCARTHY JH, HERRINGTON i: Bone aluminum in

haemodialyzed patients and in rats injected with aluminum chloride: Relationship to impaired bone mineralization. J C!in Paiho! 32:832—844, 1979 16. ROBERTSON iA, FELSENFELD Ai, HAY000D CC, WILSON P, CLARKE C, LLACI-I F: An animal model of aluminum induced

osteomalacia: Role of chronic renal failure. Kidney mt. in press 17. CHAN Y, ALFREY AC, POSEN S. LISSNER D, HILLS E, DUSTAN C,

EVANS R: Effect of aluminum on normal and uremic rats: Tissue

370

Andress et a! distribution, vitamin D metabolites, and quantitative bone histolo-

25. ELLI0Tr HL, DRYBURGH F, FELL SO, SABET 5, MACDOUGALL Al:

gy. Calcif Tissue In! 35:344—351, 1983 18. ALFREY AC, HEGG A, CARSWEL P: Metabolism and toxicity of aluminum in renal failure. Am J Clin Nuir 33:1509—1516, 1980 19. CANN CE, PRUSSIN SG, GORDON GO: Aluminum uptake by the

Aluminum toxicity during regular haemodialysis. Br Med J 1:1101— 1103, 1978

parathyroid glands. J

Gun Endocrinol Metab 49:543—545, 1979

20. GERTNER JM, BROADUS AE, ANAST CS, GREY M, PEARSON H,

26. WALKER OS, AARON JE, PEACOCK M, ROBINSON PJA, DAVISON

AM: Dialysate aluminum concentration and renal bone disease. Kidney In! 21:41 1—415, 1982 WD, HEGG AP, ALFREY AC: Gastrointestinal absorption

27. KAEHNY

GENEL M: Impaired parathyroid response to induced hypocalcemia

of aluminum from aluminum-containing antacids. N Engi J Med

in thalassemia major. J Pediatr 95:210—213, 1970 21. HODSMAN AB, SI-IERRARD DJ, ALFREY AC, OTT 5, BRICKMAN AS, MILLER NL, MALONEY NA, COBURN JW: Bone aluminum and

28. RECKER RR, BLOTCKY AJ, LEFFLER JA, RACK EP: Evidence for

histomorphometric features of renal osteodystrophy. J

Clin Endo-

crinol Metab 54:539—546, 1982

22. COURNOT-WITMER 0, ZINGRAFF J, BOURDON R, DRUEKE T, BALSAN S: Aluminum and dialysis bone-disease. Lance! 2:795—796, 1979 23. MALLUCHE HH, AKMAL M, MAYER E, NORMAN A, MASSRY SO,

FRIEDLER RM: Parathyroid hormone is needed for the positive effect of I ,25(OH)2 Vitamin D on bone formation and mineralization in uremia (abstract). Calcif Tissue mt (suppl l)34:S55, 1982 24. PLATFS MM, GOODE GC, HIsLOP JS: Composition of the domestic

water supply and the incidence of fractures and encephalopathy in patients on home dialysis. Br Med J 2:657—660, 1977

296:1389—1390, 1977

aluminum absorption from the gastrointestinal tract and bone deposition by aluminum carbonate ingestion with normal renal function. fLab Clin Med 90:810—815, 1977 29. RITz E, MALLUCHE HH, KREMPIEN B, MEHLS 0: Calcium metab-

olism in renal failure, in Disorders of Mineral Metabolism: Pathophysiology of Calcium, Phosphorus, and Magnesium, edited by Bonner F, Coburn JW, New York, Academic Press, vol. 3, 1981, pp. 151—250

30. HOLTROP ME, KING GJ: The ultrastructure of the osteoclast and its functional implications. Cliii Orthop 123:177—196, 1977 31. KREMPIEN B, RITZ E, GLOEDE 1: Effects of PTH on osteocytes ultrastructural evidence of anisotropic osteolysis and involvement of the cytoskeleton. J Metabol Bone Dis 1:55—67, 1978