Effect of administering calcium carbonate to treat secondary hyperparathyroidism in nondialyzed patients with chronic renal failure

Effect of Administering Calcium Carbonate to Treat Secondary Hyperparathyroidism in Nondialyzed Patients With Chronic Renal Failure Yusuke Tsukamoto,

MD, Rika Moriya, MD, Yasusi Nagaba, MD, Tetsuo Morishita, MD, lbuki Izumida, MD, and Michihito Okubo, MD

0 We administered calcium carbonate orally to determine its safety and efficacy in treating nondialyxed patients with mild to moderate renal failure and secondary hyperparathyroidism. Twenty patients with chronic renal failure (creatinine clearance levels ranging from 7.9 to 42.7 mUmin) participated in this study. After a g-month control period, 3 g calcium carbonate was administered daily for 6 months. We studied the effect for another 6 months after discontinuation of the regimen. We found that serum-intact parathyroid hormone was suppressed from 163 2 149 pg/mL to 65 ? 61 pg/mL (f < 0.05) by treatment. This suppression was achieved with no increase in serum concentrations of 1,25(OH)*D3. Serum phosphorus levels decreased from 3.4 2 0.7 to 3.0 ? 0.7 mg/dL (P < 601) and Ca2+ concentration increased significantly from 2.40 t 0.12 mEq/L to 2.57 ? 0.06 mEq/L (P < 0.001) at 6 months. These changes were reversed after the 6-month period of withdrawal from calcium carbonate. Deterioration of renal function was not exacerbated by the therapy. Calcium carbonate administration also suppressed the serum concentrations of alkaline phosphatase and osteocalcin, indicating that improvement of hyperparathyroid bone disease is possible without a vitamin D3 supplement at an earlier stage of renal failure. Thus, administration of 3 g oral calcium carbonate daily was highly effective in treating secondary hyperparathyroidism in patients with mild to moderate renal failure. 0 1995 by the National Kidney Foundation, Inc. INDEX WORDS: Secondary phosphate binder.

hyperparathyroidism;

chronic

renal

M

ANY uremic patients receiving chronic hemodialysis develop osteitis fibrosa due to secondary hyperparathyroidism.’ Once the hyperparathyroidism becomes established and high serum parathyroid hormone (PTH) levels are demonstrated, it becomes difficult to suppress a secretion of PTH to normal range only with the daily administration of phosphate binders combined with vitamin D3.2 One of the major reasons for this difficulty is that these patients require relatively high PTH levels to maintain a normal rate of bone formation,3 and suppression of PTH secretion into a “normal level” of healthy control often causes hypercalcemia and adynamic bone. We confirmed this finding by the study of oral 1,25(OH),D, pulse therapy, which produced hypercalcemia only when the serum levels of alkaline phosphatase returned to normal.4 All these results indicate that these patients develop a skeletal resistance to PTH.5-7 Another reason is the development of severe hyperplasia of parathyroid glands, with possible adenomatous monoclonal proliferation at least in some cases.* To prevent secondary hyperparathyroidism during end-stage renal failure, treatment should be started before such a severe hyperplasia of parathyroid glands develops. Oral calcitriol administration is one type of treatment for this purpose. Recent double-blind studies demonstrated American

Journal

of Kidney

Diseases,

Vol 25, No 6 (June),

failure;

calcium

carbonate;

parathyroid

hormone;

that the administration of low doses of calcitriol at this stage of uremia was effective in suppressing PTH secretion and did not exacerbate the deterioration of renal function when hypercalcemia was prevented.g-‘l These results disagreed with the conclusions of earlier reports.‘2z’3 These earlier studies used higher doses of vitamin D3 in patients with more severe renal failure (<20 mL/min of glomerular filtration rate), which often caused hypercalcemia and hyperphosphatemia. Oral administration of phosphate binder is another treatment of choice. Foumier et al first demonstrated that 3 g calcium carbonate with a nonhypercalcemic dose of 25(OH)D3 was effective in decreasing serum C-terminal PTH levels and improving bone histology.14 However, it has

From the Department of Medicine, Kitasato University School of Medicine, Kanagawa; and Sane-Kousei Hospital, Tochigi, Japan. Received September 8, 1994; accepted in revisedform February 14, 1995. Supported by the Program Project Grantfrom the Ministry of Health and Welfare of Japan. Address reprint requests to Yusuke Tsukamoto, MD, Department of Medicine, Kitasato University School of Medicine, 1-1.5-I Kitasato, Sagamihara, Kanagawa 228, Japan. 0 I995 by the National Kidney Foundation, Inc. 0272~6386/95/2506-0009$3.00/O 1995:

pp 879-886

879

880

TSUKAMOTO

never been determined whether calcium carbonate is effective without any vitamin D3 regimen in suppressing PTH secretion at an early stage of uremia, when most patients show normal serum concentrations of both phosphorus and calcium. To determine whether administering calcium carbonate is effective when serum phosphorus levels remain in the normal range, we administered 3 g calcium carbonate daily for 6 months to 20 nondialyzed patients with mild to moderate renal failure. MATERIALS

AND

METHODS

We studied 20 nondialyzed patients with chronic renal failure (10 men and 10 women) ranging in age from 3 1 to 75 years (mean, 52 -L. 12 years). Chronic glomerulonephritis was the cause of the underlying renal failure in all cases. The serum creatinine levels ranged from 2.0 to 5.2 mg/dL (mean, 3.2 +- 1.0 mg/dL) and creatinine clearance ranged from 7.9 to 42.7 mL/min (22.9 C 9.8 mL/min). Compliance with the medication regimen and diet instruction were criteria for participation in the study. The patients were instructed to follow a 35 calikg body weight diet that contained 0.8 g/kg body weight protein and 600 mg phosphorus. A dietitian interviewed the patients every month during the study period. Informed consent for participation was obtained from all patients. Since a double-blind, placebo-controlled study was considered unethical in these patients, the study was designed and conducted in three periods, as follows. During a 6-month control period (stage 1 to stage 2), the patients discontinued any treatment that could affect calcium metabolism, including phosphate binder and vitamin D3. Eleven patients were receiving calcitriol or 1-2(alpha) calcidol during stage 1. In the second 6-month period (stage 2 to stage 4), 3 g calcium carbonate was administered three times a day with meals. In the third B-month period (stage 4 to stage 5), calcium carbonate,was discontinued. No vitamin D3 regimen was administered during any period. Serum concentrations of total calcium, ionized calcium, phosphorus, creatinine, urea nitrogen, albumin, alkaline phosphatase, PTH, and 1,25(OH)ZD, were determined at the beginning and end of each period, as well as at the beginning of the fourth month of the second period (stage 3). Serum osteocalcin concentrations were determined at stages 2 and 3. Three patients were excluded from the study after stage 4 because they were started on hemodialysis. Six patients failed to return for required testing at stage 5. Thus, renal function was evaluated at stage 5 in the remaining 11 patients. Serum concentrations of calcium (corrected by albumin concentrations), phosphorus, creatinine, urea nitrogen, and alkaline phosphatase were determined with an AutoAnalyzer (Hitachi Instruments, Tokyo, Japan). Serum concentration of PTH was measured with a kit (Allegro intact PTH kit; Japan MediPhysics Inc, Tokyo, Japan) that recognizes an intact molecule of PTH.” Serum levels of osteocalcin were measured with a kit (Intact osteocalcin kit; Teijin Co, Tokyo, Japan) that recognizes an intact molecule of osteocalcin by

ET AL

immunoradiometric assay. I6 High-performance liquid chromatography was used to measure serum concentrations of 1,25(OH)2D3.‘7 The serum concentration of ionized calcium (Ca’+) was measured by the ion-sensitive electrode method. Results were expressed as mean values ? SD. Data collected at the various stages of the study were analyzed by paired t-tests using a program for the Macintosh computer (StatView 4.0; Abacus Concepts, Berkeley, CA). P < 0.05 was considered statistically significant.

RESULTS

Table 1 summarizes the results of this study. Serum phosphorus concentrations increased significantly from 3.1 ? 0.8 mg/dL to 3.4 + 0.7 mg/dL (P < 0.05) between stages 1 and 2 (control period) and were significantly suppressed to 3.0 + 0.7 mg/dL (P < 0.01) during the first 3 months of calcium carbonate administration. However, no further suppression occurred during the next 3 months of its administration. No significant difference in serum phosphorus concentrations was detected after the 6-month withdrawal from calcium carbonate at stage 3. Serum Ca” concentrations decreased significantly from 2.58 + 0.08 mEq/L to 2.40 rt 0.12 mEq/L (P < 0.001) during the control period and increased significantly to 2.57 + 0.08 mEq/L (P < 0.0001) during the administration of calcium carbonate for 3 months. No significant change was observed during the next 3 months of calcium carbonate administration. Serum Ca2+ concentration decreased significantly from 2.56 + 0.12 mEq/ L to 2.43 5 0.1 rnJ?q/L (P < 0.01) between stages 4 and 5. Serum concentrations of intact PTH increased significantly from 108 + 71 pg/mL to 183 + 149 pg/mL (P < 0.05) during the control period and decreased significantly to 85 ?I 61 pg/mL (P < 0.001) during the first 3 months of calcium carbonate administration (Fig 1). There was no significant change during the next 3 months of calcium carbonate treatment. Serum intact PTH concentrations again significantly increased with discontinuation of calcium carbonate from stage 4 to 5 (P < 0.001). The response of serum alkaline phosphatase activity paralleled the change in serum intact PTH concentration (Table 1). Serum osteocalcin concentrations also were significantly suppressed from stage 2 to 3 (P < 0.001). Serum concentrations of 1,25(OH),D, decreased from 57.4 ? 18 pg/mL to 18.5 2 6.8 pg/mL (P < 0.0001) during the control period (Table 1).

ADMINISTRATION

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Table

IN NONDIALYZED

1. Summary

of Blood

Chemistry

Data

(m$lL)

WY-)

No. of Patients

BUN (mg/dL)

Cr (mg/dL)

Stage 1

20

39 t 18

3.2 + 1.0

8.5 2 0.4

2 3 4

20 20 20

43 2 IO* 44 k 11 48 -t 14

3.7 + I.lT 4.2 t 1.4-t 4.7 2 1.8$

5

11

50 + 18 8-18

Normal

range

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During

Ca*+

the

Five

Stages

(mgYdL)

Al-p (M/L)

PTH

2.58 t 0.08

3.1 +- 0.8

196 r 70

8.4 t- 0.4 8.5 ? 0.5 8.6 k 0.6

2.40 + 0.12T 2.57 t 0.08T 2.56 +. 0.12

3.4 + 0.7* 3.0 + 0.7’ 3.3 2 0.7

220 ? 68$ 201 + 71* 196 t 117

108 (n 183 8.5 83

5.2 ? 2.1*

8.4 + 0.5

2.43 ir O.l$

3.7 + 0.7

216 2 67*

233 ? 140T

0.6-I .2

8.2-10.4

2.2-2.5

1.8-4.8

go-240

5-60

(PcdmL)

? = ? + 2

71 15) 149 6lt 64

Abbreviations: BUN, blood urea nitrogen; Cr, serum creatinine; Ca, serum total calcium; Ca’+, plasma ionized Al-p, alkaline phosphatase; 1 ,25D3, serum 1 ,25(OH)*D3; BGP, serum intact osteocalcin; ND, not determined. l P < 0.05 v previous stage by paired t-test. T P < 0.001 v previous stage by paired t-test. $ P i 0.01 Y previous stage by paired f-test.

6 250E 200a IJ 150g loo-

t I

1

-6

-3

’

Duration

0

’

of therapy

3

’

6

’

12

(month)

Fig 1. Changes in serum concentrations of intact PTH during the study. ‘Significant versus stage 1 (P < 0.05), #significant versus stage 2 (P < O.OOl), *‘significant versus stage 4 (P < 0.001).

57 (n 18 17 20 (n

t 18 = 15) + 7-f -+ 9 2 10 = 17) ND

20-80 calcium;

BGP (W-W

ND 21.9 +- 11.3 12.8 + 1OT ND ND 1.8-8.6 P, phosphorus;

DISCUSSION

,300-

”

1,25D3 (w/W

4. Figure 4 illustrates the significant negative correlation between concentrations of intact PTH and Ca” at stages 4 and 5. No significant correlation between serum concentrations of intact PTH and total calcium was detected at either stage. Serum concentrations of intact PTH also correlated negatively with serum concentrations of 1,25(OH),DIi at stages 1 and 2 but not at stage 4 (Fig 5).

There were no significant changes in serum 1,25(OH)*D3 concentrations during calcium carbonate administration (18.5 + 6.8 pg/mL v 17.4 + 9.2 pg/mL v 19.8 2 10.3 pg/mL). Figure 2 illustrates the change in serum creatinine and l/ creatinine ratio. The slope of both the serum creatinine and lkreatinine ratio changed after the withdrawal of calcium carbonate. To determine which factors regulated a secretion of PTH, we studied the correlations between serum concentrations of intact PTH and other serum factors. Figure 3 shows the correlation between serum concentrations of intact PTH and phosphorus. Significant positive correlations were found at stages 1, 2, and 5, but not at stage

50-

of Study

’

Correction of hyperphosphatemia by the suppression of dietary phosphorus load is an accepted method of treating secondary hyperparathyroidism in patients with end-stage renal failure. Oral aluminum hydroxide is prescribed for this purpose. Recently, calcium carbonate has been used instead to prevent and treat aluminuminduced complications. However, calcium carbonate is a less-effective phosphate binder than aluminum hydroxide. is,19The oral administration of calcium carbonate, particularly in combination with vitamin D3 regimens, often causes hypercalcemia and increases the serum calcium/phosphorus product in dialysis patients.” Despite these limitations, calcium carbonate is the treatment of choice at the present time. Many clinical triaIs have demonstrated both the efficiency and the limitations of calcium carbonate therapy in patients on dialysis, 21-24but we are unaware of any published studies regarding the use of calcium carbonate without any vitamin D3 regimen in nondialyzed patients with chronic renal failure.

TSUKAMOTO

ET AL

0.45 0.40.358

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0.1 0.05 -3

0

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Duration of therapy (month)

Duration of therapy (month)

The present study demonstrates that oral administration of calcium carbonate without the administration of calcitriol effectively suppressed the secretion of PTH in patients with mild to moderate renal failure. Their serum concentrations of 1,25(OH)*D3 were suppressed below normal when calcium carbonate administration was initiated and did not increase over the course of such treatment. This result agrees well with the results obtained by Lucas et a1,25 but does not agree with the results obtained by both Llach and Massryz6 and Portale et aLz7 which demonstrated a successful restoration of serum

stage 1 6001~

Fig 2. Changes in serum concentrations of creatinine and llcreatinine during the study. This figure includes only the data of the 11 patients who were followed throughout the study.

1,25(OH),D, level by the phosphorus restriction diet. The reason for this discrepancy of conclusions is quite clear. The patients in the study by Llach and Massry showed serum concentrations of 1,25(OH)*D3, which were above those of the levels of healthy controls (> 100 pmol/L).26 The patients in the study by Portale et al showed similar serum concentrations of 1,25(OH)*D3, but they investigated the effect of phosphate restriction for only 6 days.” Thus, it is clear that the restoration of serum 1,25(OH)*D3 concentration is possible only for the patients at a very early stage of uremia.

stage 2 ’

stage 4

stage 5

600

600

500

500 % 400 !

Fig 3. Correlations between concentrations of serum phosphorus and intact PTH at each stage of study. Serum concentrations of intact PTH were positively correlated with serum concentrations of phosphorus at stage 1 (beginning of pretreatment; r = 0.66, P < 0.01, n = 15), stage 2 (beginning of treatment; r = 0.49, P < 0.05, n = 29), and stage 5 (end of posttreatment; r = 0.52, P < 0.05, n = 11) but not at stage 4 (end of treatment; r = 0.25, n = 20) of the study.

ADMINISTRATION

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IN NONDIALYZED

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stage 1

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stage 2 600

600

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PTH at each stage of the study. Serum Fig 4. Correlation between serum concentrations of Ca2+ and intact concentrations of intact PTH correlated significantly with plasma concentrations of Ca*+ at stage 4 (end of treatment; r = -0.56, P < 0.01, n = 20) and stage 5 (end of post-treatment; r = -0.66, P < 0.05, n = 11). Other correlation coefficients were -0.26 at stage 1 (beginning of pretreatment; n = 15) and 0.01 at stage 2 (beginning of treatment; n = 20). Two data points are overlapped in the panel depicting stage 4.

the period that was free of any calcium-regulating regimen, serum concentrations of intact PTH correlated positively with serum phosphorus concentrations and negatively with serum concentrations of 1,25(OH)zD,. However, there was no significant correlation with the serum concentra-

Although it is virtually impossible to judge which factors predominate in suppressing the secretion of PTH in this clinical setting, factor analysis provided some clues. The correlation between serum concentrations of intact PTH and other factors varied according to stage. During

stage 1

stage 4 6007

600 z500$40055 5 300z & 5 2 -

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300 0

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1020304050607080901

1,2503 (pg/ml)

l

1

t

0 IA 0

10

20

30

40

1,25D3 (pg/ml)

0

10

20

30

40

50

1,25D3 (pgiml)

Fig 5. Correlation between serum concentrations of 1,25(0H),Ds and intact PTH at each stage of the study. Serum concentrations of intact PTH correlated significantly with serum concentrations of 1,25(OH)2D3 only at stage 2 (beginning of treatment; r = -0.52, P < 0.01, n = 20). Other correlation coefficients were 0.43 at stage 1 (beginning of pretreatment; n = 15) and 0.05 at stage 4 (end of treatment; n = 17).

884

tions of Ca2+ during this period. Calcium carbonate administration completely altered these correlations. The correlation between serum concentrations of intact PTH and concentrations of either serum phosphorus or 1,25(OH)2D3 became insignificant at stage 4. In turn, correlations between the serum concentrations of Ca2+ and serum concentrations of PTH became significant at stage 4. These results indicate that concentrations of both serum 1,25(OH)2D3 and of phosphorus were more important determinants of PTH secretion than Ca2+ concentrations in the absence of an oral calcium carbonate administration. Positive correlations appeared again after calcium carbonate was withdrawn (stage 5), suggesting that this change was not caused by a further deterioration of renal function. Serum Ca2’ concentrations became the dominant determinant of PTH secretion on administration of calcium carbonate. Since the effects of Ca” concentration on PTH secretion continued through stage 5, we could not determine whether it was calcium carbonate or deterioration of renal function that caused this change. Calcium carbonate administration was highly effective in suppressing PTH secretion even at the stage at which serum concentrations of calcium and phosphorus remained in the normal range. An average healthy Japanese person’s dietary intake of phosphorus is approximately 800 mg. According to a report by She&h et al, the oral administration of 2.52 g calcium carbonate containing 50 mEq calcium could extract 196 mg from 347 mg of phosphorus.r* Since the patients in our study were instructed to maintain a dietary phosphorus intake of 600 mg, administration of 3 g calcium carbonate theoretically could reduce the dietary phosphorus intake to approximately 400 mg. Since it is not easy to restrict phosphorus intake to that extent solely by diet, taking oral calcium carbonate makes this restriction easier to achieve. Three grams of calcium carbonate increased the serum calcium concentrations, but none of the patients showed levels higher than 9.7 mg/dL, and the majority did not exhibit levels above 9 mg/ dL. Deterioration of renal function was not exacerbated by calcium carbonate. Some studies have demonstrated an improved glomerular filtration rate with phosphorus restriction.28M30Although the study period was too short to evaluate the effect of calcium carbonate on renal function, it appeared to be an effective therapeutic approach.

TSUKAMOTO

ET AL

The serum concentrations of both osteocalcin and alkaline phosphatase increased even in those patients who had mild to moderate renal failure. Osteocalcin is a bone Gla protein secreted by the osteoblasts.3’y32The exact role of this protein has not been established, but a positive correlation has been demonstrated between its serum concentrations and osteoblastic activity.33,34Although serum alkaline phosphatase is composed of isoenzymes produced in the intestine, liver, kidney, and bone, measurement of serum levels can provide an indication of increased osteoblastic activity in bone.35 The increase in the serum concentrations of both substances in the majority of our patients suggests they had developed from hyperparathyroid bone disease. A bone biopsy study already has demonstrated that hyperparathyroid bone started to develop in patients with a glomerular filtration rate of 30 mL/min.36 Since oral calcium carbonate was effective in suppressing both serum intact osteocalcin and alkaline phosphatase levels, the bone changes due to hyperparathyroidism were expected to improve in this study. The potential risk associated with this therapy is the development of adynamic bone disease due to excess suppression of PTH levels, which is a well-known fact in dialysis patients.’ Hernandez et al recently reported that 30 of 92 nondialyzed patients with end-stage renal failure also exhibited adynamic bone without a stainable bone aluminum.37 This study demonstrated that patients with adynamic bone disease were older and had lower serum intact PTH compared with non-adynamic bone patients (179 ? 3 1 pg/mL v 432 + 62 pg/mL). It is obvious from this study that these patients require much higher PTH levels than healthy person to maintain a normal bone turnover. However, the patients with higher glomerular filtration rate require much lower PTH levels. Bianchi et al suppressed mean serum intact PTH levels from 109 to 81.6 pg/mL by the combined administration of calcitriol and calcium carbonate in nondialyzed patients with creatinine clearance levels between 64 and 36 mL/min.38 Histology revealed no occurrence of adynamic bone disease in these patients at the end of therapy. Thus, bone resistance to PTH is minimum in patients with mild renal failure. Since some of the patients in our study showed lower creatinine clearance levels, higher PTH levels would be required to maintain a normal bone turnover.

CACO,

ADMINISTRATION

IN NONDIALYZED

UREMICS

In conclusion, oral calcium carbonate therapy was highly effective in suppressing the secretion of FTH in patients with mild to moderate renal failure. It appeared to be a safe treatment in terms of renal function, but it should be emphasized that an excess suppression of PTH levels would cause adynamic bone disease, especially in patients with advanced renal failure. ACKNOWLEDGMENT The authors are grateful to Dr Kenji Hosoda, Institute for Biomedical Research, Teijin Ltd, Tokyo, Japan, for the assay of serum intact osteocalcin.

REFERENCES 1. Sherrard DJ, Hertz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure-An evolving disorder. Kidney Int 43:436-442, 1993 2. Llach F: Parathyroidectomy in chronic renal failure: Indications, surgical approach and the use of calcitriol. Kidney Int 38:S62-S68, 1990 (suppl) 3. Andress DL, Endres DB, Maloney NA, Kopp JB, Cobum JW, Sherrard DJ: Comparison of parathyroid hormone assays with bone histomorphometry in renal osteodystrophy. J Clin Endocrinol Metab 63:1163-1169, 1986 4. Tsukamoto Y, Moriya R, Nomura Y, Sato N, Faugere MC, Malluche HH: Long-term effect of oral calcitriol pulse therapy on bone in hemodialysis patients. Bone 14:421-425, 1993 5. Ritz E, Malluche HH, Krempien B, Tschope W, Massry SG: Pathogenesis of renal osteodystrophy: Roles of phosphate and skeletal resistance to PTH. Adv Exp Med Biol 103:423-436, 1978 6. Massry SG, Stein R, Garty J, Arieff AI, Cobum JW, Norman AW, Friedler RM: Skeletal resistance to the calcemic action of parathyroid hormone in uremia: Role of 1,25 (OH)*D3. Kidney Int 9:467-474, 1976 7. Massry SG: Skeletal resistance to the calcemic action of parathyroid hormone: Role of the kidney and vitamin D. Contrib Nephrol 13:125-131, 1978 8. Falchetti A, Bale AE, Amorosi A, Bordi C, Cicchi P, Bandini S, Marx SJ, Brandi ML: Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11. J Clin Endocrinol Metab 76:139-144, 1993 9. Coen G, Mazzaferro S, Bonucci E, Ballanti P, Massimetti C, Donato G, Landi A, Smacchi A, Della RC, Cinotti GA: Treatment of secondary hyperparathyroidism of predialysis chronic renal failure with low doses of 1,25(OH),D,: Humoral and histomorphometric results. Miner Electrolyte Metab 12:375-382, 1986 10. Nordal KP, Dahl E: Low dose calcitriol versus placebo in patients with predialysis chronic renal failure. J Clin Endocrinol Metab 67:929-936, 1988 11. Baker LRI, Louise Abrams SM, Roe CJ, Faugere M-C, Fanti P, Subayti Y, Malluche HH: 1,25(OH),D, administration in moderate renal failure: A prospective double-blind trial. Kidney Int 35:661-669, 1989

12. Christiansen C, Rodbro P, Christensen MS, Hartnack B, Transbol I: Deterioration of renal function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol. Lancet pp 700-703, 1978 13. Tougaard L, Sorensen E, Brochner MJ, Christensen MS, Rodbro P, Sorensen AW: Controlled trial of laphahydroxycholecalciferol in chronic renal failure. Lancet 1:1044-1047,

1976

14. Foumier A, Idrissi A, Sebert JL, Gueris J, Garabedian M, Renaud H, Westeel PF: Preventing renal bone disease in moderate renal failure with CaCOr and 25(OH) vitamin DS. Kidney Int 24:S178-S179, 1988 (suppl) 15. Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan GL, Nozawa-Ung K, Kim LY, Keutmann HT, Wang C-A, John T, Potts J, Segre GV: Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 33: 13641367, 1987 16. Hosoda K, Eguchi H, Nakamoto T, Kubota T, Honda H, Jindai S, Hasegawa R, Kiyoki M, Yamaji T, Shiraki M: A sandwich immunoassay for intact human osteocalcin. Clin Chem 38:2233-2238, 1992 17. Leenheer AP, Bauwens RM: Comparison of a cytosol radioreceptor assay with a radioimmunoassay for 1,25-dyhydroxyvitamin D in serum or plasma. Clin Chim Acta 152: 143154, 1985 18. Sheikb MS, Maguire JA, Emmett M, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS: Reduction of dietary phosphorus absorption by phosphorus binders: A theoretical, in vitro, and in vivo study. J Clin Invest 83:66-73, 1989 19. Delmez JA, Slatopolsky E: Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 19:303-317, 1992 20. Schaefer K, Umlauf E, von Herrath D: Reduced risk of hypercalcemia for hemodialysis patients by administering calcitriol at night. Am J Kidney Dis 19:460-464, 1992 21. Slatopolsky E, Weerts C, Lopez HS, Norwood K, Zink M, Windus D, Delmez J: Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 3’15:157-161, 1986 22. Hertz G, Andress DL, Norris KC, Shinaberger JH, Slatopolsky EA, Sherrard DJ, Cobum JW: Improved bone formation in dialysis patients after substitution of calcium carbonate for aluminum gels. Trans Assoc Am Phys 100: 139146, 1987 23. Turner C, Compston J, Mak RH, Vedi S, Mellish RW, Haycock GB, Chantler C: Bone turnover and 1,25-dihydroxycholecalciferol during treatment with phosphate binders. Kidney Int 33:989-995, 1988 24. Foumier A, Moriniere P, Ben HF, el Esjer N, Shenovda M, Ghazali A, Bouzemidj M, Achard JM, Westeel PF: Use of alkaline calcium salts as phosphate binder in uremic patients. Kidney Int 42:S50-S61, 1992 (suppl) 25. Lucas PA, Brown RC, Woodhead JS, Coles GA: 1,25Dihydroxycholecalciferol and parathyroid hormone in advanced renal failure: Effect of simultaneous protein phosphorus restriction. Clin Nephrol 25:7-10, 1986 26. Llach F, Massry SG: On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 61:601-606, 1985

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27. Portale AA, Booth BE, Halloran BP, Morris RC Jr: Effect of dietary phosphate on circulating concentrations on 1,25dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73:1580-1589, 1984 28. Ibels LS, Alfrey AC, Haut L, Huffer WE: Preservation of function in experimental renal disease by dietary restriction of phosphate. N Engl J Med 298:122-126, 1978 29. Karlinsky ML, Haut L, Buddington B: Preservation of renal function in experimental glomerulonephritis. Kidney Int 17:293-302, 1982 30. Lumlertgl D, Burket J, Gillum DM: Phosphate depletion arrests progression of chronic renal failure independent of protein intake. Kidney Int 29:658-666, 1986 3 1. Lian JB, Friedman PA: The vitamin K-dependent synthesis of y-carboxyglutamate, in mineralized tissue. J Biol Chem 253:6623-6626, 1978 32. Nishimoto SK, Price PA: Secretion of the vitamin Kdependent protein of bone by rat osteosarcoma cells. J Biol Chem 255:6579-6583, 1980 33. Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier PJ: Serum bone Gla protein, a specific marker

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for bone formation in postmenopausal osteoporosis. Lancet 19:1091-1093, 1984 34. Charhon SA, Delmas PD, Malaval L, Chavassieux PM, Arlot M, Chapuy MC, Meunier PJ: Serum bone Glaprotein in renal osteodystrophy: Comparison with bone histomorphometry. J Clin Endocrinol Metab 63:892-897, 1986 35. Naik RB, Gosling P, Price CP: Comparative study of alkaline phosphatase isoenzymes, bone histology, and skeletal radiography in dialysis bone disease. BMJ 1:1307-1310, 1977 36. Malluche HH, Ritz E, Lange HP, Kutschera L, Hodgson M, Seiffert U, Schoeppe W: Bone histology in incipient and advanced renal failure. Kidney Int 9:355-362, 1976 37. Hemandez D, Conception MT, Lorenzo V, Martinez ME, Rodriguez A, De Bonis E, Gonzalez-Posada JM, Felsenfeld AJ, Rodriguez M, Torres A: Adynamic bone disease with negative aluminum staining in predialysis patients: Prevalence and evolution after maintenance dialysis. Nephrol Dial Transplant 9:517-523, 1994 38. Bianchi ML, Colantonio G, Campanini F, Rossi R, Vale& G, Ortolani S, Buccianti G: Calcitriol and calcium carbonate therapy in early chronic renal failure. Nephrol Dial Transplant 9:1595-1599, 1994