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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 512-519
Copyright © 1999 by The Endocrine Society

Original Studies

Bone Mass and Dynamic Parathyroid Function According to Bone Histology in Nondialyzed Uremic Patients after Long-Term Protein and Phosphorus Restriction

Marie-Helene Lafage-Proust, Christian Combe, Nicole Barthe and Michel Aparicio

Faculté de Médecine, Laboratoire de Biologie du Tissu Osseux (M.-H.L.-P.), Saint-Etienne; and Maladies Médicales des Reins (C.C., M.A.) and Service de Médecine Nucléaire (N.B.), Hôpital Pellegrin-Tripode, Bordeaux, France

Address all correspondence and requests for reprints to: Dr. Marie-Helene Lafage-Proust, Faculté de Médecine, Laboratoire de Biologie du Tissu Osseux, 15 rue A Paré, 42023 Saint Etienne Cedex 2, France. E-mail: lbto{at}univ-st-etienne.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
One year of a very low protein diet (VLPD) can reverse secondary hyperparathyroidism in uremic patients. We studied bone histology, bone mineral density (BMD), and dynamic parathyroid function (calcium/PTH curves) in 16 nondialyzed patients with advanced renal failure who had been receiving a VLPD for a mean of 5 yr (mean protein intake, 0.34 ± 0.12 mg/kg·day; mean phosphorus intake, 8.2 ± 2.1 mg/kg·day) and daily supplementation with essential amino acids and their ketoanalogs (1000 IU vitamin D2 and 1–2 g calcium carbonate). Three patients exhibited a high bone formation rate (BFR), 7 patients had normal bone remodeling, and 6 patients had a low BFR, including 2 with osteomalacia and 4 with adynamic bone disease without aluminum overload. A longer diet duration and lower caloric intake were associated with low BFR. More than half of the patients exhibited moderate or severe osteoporosis at the appendicular skeleton. The t score of femur BMD explained 65% of the BFR variance. Patients with a low BFR had a dynamic parathyroid function similar to that of patients with a normal BFR, except they had a lower capacity to buffer a calcium load, whereas patients with a high BFR had a higher basal PTH/maximum PTH and a steeper calcium/PTH curve slope; the calcium set-point was identical in the three groups.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FOR DECADES, osteitis fibrosa was reported as the most frequent form of renal osteodystrophy, whereas osteomalacia was usually associated with aluminum overload. Since the mid-1980s, an adynamic bone disease (ABD) without aluminum deposits was described in uremic patients (1, 2) with an increasing incidence that reached 48% in a recent study (3). One of the most likely explanations for the development of such an adynamic lesion, which had never been previously reported (4), could be an oversupression of PTH secretion by calcium salts proposed as new dietary phosphate binders or by vitamin D sterols. Although the morbidity of ABD is not clearly established, some researchers reported an increase in hypercalcemia episodes and risk of fractures (5).

The correction of secondary hyperparathyroidism (2nd HPT) can also be obtained by reducing dietary phosphate through increased plasma calcitriol levels in patients with moderate renal failure (6, 7) or through a direct effect on PTH synthesis and secretion, independent of calcium and calcitriol levels, in advanced renal failure, as shown by experimental (8) and clinical studies (9, 10, 11, 12). In the rat, it was showed that dietary phosphate might regulate PTH gene expression through a stabilization of PTH messenger ribonucleic acid, independently of calcium or calcitriol levels (13, 14, 15). Under these conditions, long term control of 2nd HPT by phosphorus restriction might be responsible for ABD. Moreover, we showed that patients with advanced renal failure submitted for 1 yr to a very low protein and low phosphorus diet (VLPD) exhibited decreases in the bone formation rate (BFR) (16). We concluded at that time that the potential risk regarding the skeleton of these patients seemed to be an excessive suppression of bone remodeling secondary to relative hypoparathyroidism, resulting in bone loss.

The aim of the present study was to determine whether ABD and osteoporosis could be observed in nondialyzed uremic patients after long term protein and phosphorus restriction. Thus, we assessed bone histology and bone mineral density in 16 patients who had been submitted to VLPD for a mean of 5 yr. At the same time, dynamic tests of the calcium/PTH relationship were performed. The relationships among bone lesions, the characteristics of the diet, and the parathyroid-gland function were analyzed to further understand the factors that might support the development of low bone turnover or bone loss.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Uremic patients with an initial glomerular filtration rate (GFR) below or equal to 18 mL/min who had been under phosphorus and protein restriction for at least 3.5 yr were included. Patients with disease known to interfere with calcium and phosphate metabolism were excluded as were those taking steroids, anticonvulsent drugs, calcitriol, aluminum-containing antacids, or other phosphate binders. Among the 180 uremic nondialyzed patients receiving the VLPD currently followed up in our unit, 16 ambulatory patients (8 males and 8 females) responded to these criteria. Six patients had chronic glomerulonephritis, 6 patients had chronic interstitial nephritis, and 4 patients had chronic renal failure (CRF) of unknown origin; none of them was diabetic. The mean age of the patients was 53.4 ± 17.3 yr; they had been receiving the VLPD for a mean of 65 ± 24.4 months (range, 43–120 months), and their mean GFR when diet was initiated was 14.6 ± 4.5 mL/min.

Diet

VLPD provided daily 0.4 g/kg protein of vegetable origin, 7–9 mg/kg inorganic phosphorus, and 300 mg calcium. The recommended caloric intake was 35 Cal/kg/day supplied 67% by carbohydrates, 30% by lipids, and 3% by proteins. The diet was supplemented with tablets of essential amino acids and ketoanalogs [Cetolog, Clintec (Amilly, France) or Ketosteril, Fresenius (Bad-Homburg, Germany)]. The daily dose was one tablet for 5 kg BW, each tablet provided, respectively, 3.4 mg (Cetolog) and 50 mg (Ketosteril) calcium. To maintain serum calcium levels between 2.1–2.5 mmol/L, calcium carbonate was given at a dose of 1–2 g/day (that is 400–800 mg elemental calcium), so that the mean daily intake of calcium provided by diet, tablets, and supplementation could be estimated at about 1500–2000 mg/day. All patients were also supplemented with iron and a multivitamin preparation providing 1000 IU vitamin D2/day.

Laboratory follow-up and renal function

At every monthly visit the following parameters were determined: 24-h urinary creatinine, urea, calcium, and phosphate and fasting plasma creatinine, urea, calcium, phosphate, bicarbonate, alkaline phosphatase. GFR, osteocalcin, intact PTH, calcidiol, and calcitriol levels were determined every 3 months. Compliance of patients with the prescribed diet was assessed by interviews after a 4-day food diary carried out at 3-month intervals and by monthly measurement of urinary urea and phosphorus excretion; protein intake was estimated by the formula of Maroni et al. (17).

The GFR was based upon the clearance of [51Cr]ethylenediamine tetraacetate (EDTA) determined from plasma and urine samples (18). During the 65 ± 24.4 months of the diet, [51Cr]EDTA clearance decreased significantly from 14.6 ± 4.5 to 9.9 ± 3.6 mL/min (range, 5.8–14.3 mL/min; P < 0.001).

Intact plasma PTH was measured using a two-site RIA. Plasma osteocalcin was assessed by RIA, and plasma calcidiol and calcitriol were measured by competitive binding assays.

Clinical tolerance and compliance

Half of the patients were able to perform full-time professional work, and none of them complained of bone pain or muscular weakness.

Despite the progression of renal failure, the weight of patients remained stable (61 ± 12.7 vs. 61.6 ± 11.8; P = NS). The mean serum protein and albumin levels were not modified during the follow-up [respectively, 62.7 ± 4.7 vs. 65.4 ± 5.7 g/L (P = NS) and 38.3 ± 3.6 vs. 40.8 ± 3.8 g/L (P = NS)].

A hypercalcemic episode with a calcium level over 2.7 mmol/L occurred only once in the 1020 patient-month survey. We did not observe any metastatic extraosseous calcifications. No patient presented calcification of small vessel (digital and arcade vessels) as assessed on x-rays of hands and feet. Medium and large vessel calcifications were, respectively, present in three and five patients from the combined three groups.

Compliance to the diet were satisfactory throughout the follow-up period. This was evidenced by comparing urinary excretion of urea and phosphate before the diet (257 ± 12.2 and 16.3 ± 2.4 mmol/24 h) to their excretion at the time of the study (70.5 ± 5.2 and 7.1 ± 2.1 mmol/24 h, respectively; P < 0.001). The mean follow-up calcium and phosphorus dietary intakes estimated by dietary interviews were, respectively, 564 and 515 mg/day (i.e. 8.4 mg/kg BW·day for the latter). The mean follow-up caloric intake was 32.3 ± 6.4 Cal/kg·day; the mean follow-up protein intake was 0.36 ± 0.10 kg BW/day.

The following investigations were performed once at the end of the study.

Bone histomorphometry

Sample preparation. After giving informed consent, patients underwent a 7.5-µm transiliac trephine biopsy (after double tetracycline labeling: demethylchlortetracyclin, 600 mg/day; 2 days on, 12 days off, 4 days on). The bone samples were immediately fixed in ice-cold, phosphate-buffered formalin (pH 7.4), dehydrated in pure acetone, and embedded in a resin made of purified glycol and methyl methacrylates. This procedure and embedding were performed at -20 and 4 C to preserve bone enzyme activities. Seven-micron thick sections were cut dry with a microtome (Polycut, Reicher, Germany) with HK3 tungsten knives. Staining for routine histomorphometry was performed by modified Mallory and Golner’s procedures on eight nonserial sections. Six additional nonserial sections were stained for the osteoclastic tartrate-resistant acid phosphatase and were counterstained with phosphomolybdic aniline blue according to a method developed in our laboratory (19). Finally, four 12-µm thick sections were analyzed under UV light for the determination of histodynamic parameters.

Measurements Measurements of bone mass and architecture parameters were performed at a x25 magnification; an automatic image analyzer (Leitz TAS+, Rockleigh, NJ) equipped with a Bosch camera coupled with a Leitz Orthoplan microscope was used to determine the bone volume (percentage of cancellous bone area) and structural indexes (trabecular bone thickness and trabecular bone number). Measurements of bone cellular parameters were performed on a semiautomatic system digitizing tablet (SummaSketch Plus, Summagraphics, Paris, France) connected to a MacIntosh LC microcomputer using a software developed in our laboratory. For parameter measurements and nomenclature see the report by Parfitt et al. (20).

Static parameters: The trabecular osteoid surface was the percentage of trabecular bone surface covered by osteoid. The mean osteoid thickness was measured at equidistant points on trabecular bone and expressed in microns. The eroded surface was expressed as a percentage of trabecular bone surface with resorption cavities, with or without osteoclasts. The osteoclastic surface was expressed as a percentage of bone surface corresponding to the eroded trabecular surface adjacent to osteoclasts. The number of osteoclasts per bone area is the ratio of the number of osteoclasts per area unit of bone tissue.

Dynamic parameters: The mineral appositional rate (MAR) in trabecular bone was obtained by dividing the distance between the midpoints of the two labels by the time interval between the labeling periods (that is, 15 days) and was expressed in microns per day. The single labeled surface (SL.S/BS) corresponded to the trabecular surface covered by a single labeling expressed as a percentage of the trabecular bone surface. The double labeled surface (DL.S/BS) corresponded to the trabecular surface covered by a double labeling, expressed as a percentage of the trabecular bone surface. The mineralizing surface was calculated using the formula MS/BS = 1/2 SL.S/BS + DL.S/BS). The BFR surface referent (BFR/BS), corresponded to the amount of new bone mineralized at the tissue level per µm2 of trabecular bone surface area per day, and was calculated using the formula: BFR/BS = (MS/BS) x MAR (µm3/µm2/day). The adjusted apposition rate (Aj. AR) was calculated using the formula: Aj. AR = [ MAR x (MS/BS)]/(osteoid surface/BS). The mineralization lag time (mean time interval between deposition and mineralization of osteoid tissue) was defined as the ratio of osteoid thickness by Aj.AR.

Bone disorders were classified as follows. Pure osteitis fibrosa (OF) was characterized by lesions related to secondary hyperparathyroidism, i.e. increased BFR (>0.083 µm3/µm2·day) and increased resorption parameters (OcS/BS, >1%). Osteomalacia (OM) was defined by a low BFR associated with an increase in osteoid thickness (>11 µm) and an increase in mineralization lag time. ABD was defined by a decreased BFR (i.e. <0.031 µm3/µm2/day, which is the lowest value seen in normal individuals (21), without increased osteoid thickness.Mixed osteopathy (OM/OF) was defined as the association of a low BFR, an increase in osteoid thickness, and increased osteoclastic surface.

Bone remodeling was considered normal (N) when the static and dynamic parameters were within the normal range. The reference values are those of Rasmussen and Bordier (22) for the static parameters and those of Vedi et al. (23) for the dynamic parameters.

Bone densitometry

Bone mass measurements were performed on a double energy x-ray densitometer Hologic QDR 4500 (Paris, France) at three different skeletal sites: femoral neck, lumbar spine (L2–L5), and distal radius. Given the heterogeneity of our population in terms of age and sex, we expressed the results in two ways: t score and z score. The t score is the number of SD above or below the peak bone mass. The peak bone mass is defined as the maximum amount of bone acquired at the end of growth (24) and is measured in 30-yr-old normal controls of the same sex at the different skeletal sites. Therefore, the t score expresses the amount of lost bone, independent of age, compared to a normal young population. Data from a normal French population were measured by Braillon et al. (25) and Duboeuf et al. (26) and were provided with the Hologic densitometer software. According to WHO (27), patients were classified as osteoporotic when the t score was below -2.5, as osteopenic when the t score was between -2.5 and -1, and as normal when the t score was above -1. The z score is the number of SD above or below the mean bone mass of healthy age- and sex-matched controls. Given the fact that aging is associated with physiological bone loss, patients with a z score of -1 or more were considered as having a bone mass related to their age, and those with a z score less than -1 exhibited a bone loss not explained by aging.

Evaluation of parathyroid function

To evaluate parathyroid function, the suppressibility of parathyroid secretion was studied by raising the calcium concentration through iv calcium infusion, whereas stimulation of the parathyroids was studied by lowering the calcium concentration using infusion of a calcium-chelating agent (28). The PTH secretion stimulation test was performed 2 days after the calcium infusion test to avoid possible artifactual assessments in relation to the hysteresis phenomenon.

Calcium infusion test. CaCl2 (100 mg/mL) was infused at a constant rate of 3 mg/kg BW·h elemental calcium over a 3-h period via a catheter inserted into a peripheral vein. During the same 3-h period, 300 mL 5% glucose were infused by the same catheter to dilute calcium and avoid vein damage. Blood samples were withdrawn from the contralateral arm at 0, 10, 20, 30, 60, 120, and 180 min after beginning calcium infusion.

PTH secretion stimulation test. A total amount of 50 mg/kg·BW Na2-EDTA (50 mg/mL) diluted in 500 mL 5% glucose was infused over a 3-h period via a catheter inserted into a peripheral vein (modified from Ref. 19). Blood samples were withdrawn from the contralateral arm at 0, 30, 60, 120, 150, and 180 minutes after beginning the Na2-EDTA infusion.

From the data obtained during hypocalcemia and hypercalcemia, individual PTH-calcium curves were constructed for each patient according to the methods of Brown (29) and Felsenfeld and Llach (30). Composite PTH-calcium curves were compiled for each histologic group from the individual curves. The terms used for the analysis of PTH-calcium curves have been defined extensively in a recent review (30): maximal PTH represents maximal stimulation of parathyroid glands, minimal PTH represents maximal inhibition of parathyroid, and the set-point of calcium is the ionized calcium concentration that corresponds to 50% maximal PTH.

Statistical analysis

The different groups defined on the basis of the histological results were compared using the nonparametric Kruskal-Wallis test, an equivalent of ANOVA, and the Mann-Whitney U test. Linear regression analyses were carried out between histological and dietary data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Bone histomorphometry

Data are summarized in Table 1Go. Patients were divided into three groups according to BFR. Seven patients had normal bone remodeling; three patients had OF, with one of them exhibiting severe lesions with a BFR at 0.412 µm3/µm2/day and 18% woven bone; and six patients had low bone turnover including four with ABD and two with OM.


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  		Table 1. Bone histomorphometric results: remodeling and mineralization parameters

 
In the low bone turnover group there was a significant decrease in trabecular number compared to that in the normal turnover group (1.9 ± 0.4 vs. 2.3 ± 0.2; P < 0.05), whereas trabecular thickness was similar in the three groups (not shown).

Evolution of calcium and phosphate metabolism parameters during the diet according to BFR at the time of the study

At the start of the dietary prescription, mean GFR, calcium, phosphate, and bicarbonate plasma levels were similar in all groups; in contrast, serum alkaline phosphatase, osteocalcin, and PTH levels were already higher in patients who displayed osteitis fibrosa at the time of the study (Table 2Go).


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  		Table 2. Serum biochemical data at baseline and after long term phosphorus and protein restriction, according to bone turnover

 
During the VLPD, renal function deteriorated slowly, with no statistical difference among the three groups. Correction of acidosis was observed in all patients, but the course of the other parameters varied according to the BFR; patients with low and normal BFR showed the same evolution. In patients with high bone turnover, serum levels of PTH, osteocalcin, and alkaline phosphatase increased, whereas serum calcium, phosphorus, and calcitriol levels did not change significantly. In patients with low and normal BFR, PTH and calcitriol levels decreased, whereas phosphate and osteocalcin levels significantly decreased by 30% and bicarbonate increased by 15% in low BFR patients.

Characteristics of the diet according to BFR

Table 3Go shows that no statistical differences were observed among the three groups when comparing mean age for the patients, diet duration, level of CRF, or daily dietary intake in phosphorus, calories, or protein. We observed a trend to a decrease in weight in the low BFR group that did not reach significance (P = 0.057). However, in the groups of patients with low and normal BFR, linear regression analysis found significant relationships with daily calorie intake (r2 = 0.37; P < 0.05), diet duration (r2 = - 0.29; P < 0.05), and the {Delta} weight (difference between weights before and after the diet; r2 = 0.45; P < 0.05).


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  		Table 3. Characteristics of the patients and their diet according to their BFR

 
Bone mass measurements

Bone densitometry data are summarized in Fig. 1Go. Although bone densitometry is not reliable for evaluating the actual bone mass in patients with osteomalacia because of the abundant nonmineralized component, we chose to include our two OM patients in the results because bone densitometry expresses the amount of calcified bone that is biomechanically effective and thus evaluates fracture risk. The t score data showed that 12 patients of 16, including patients with normal bone remodeling, exhibited either severe or moderate bone loss at the femoral neck, 8 of 16 did so at the radius, and 7 of 16 did so at the spine. Therefore, bone loss occurred less frequently at the spine than at the appendicular skeleton. Two patients with ABD exhibited severe bone loss at the three sites, whereas only one patient with ABD had normal femoral bone mass. Linear regression analysis showed a positive relationship between t scores at the radial and femoral sites, whereas no correlation was observed with that at the spine (r = 0.75; P < 0.002), indicating that the rates of bone loss were similar at the appendicular sites. The z score data showed that half of the patients a bone mass lower than that expected for their age. Two patients with ABD were in this group at the three skeletal sites. In the two groups of patients with low or normal turnover, we found a positive relationship BFR and z score or t score at the femoral neck (r2 = 0.25; P < 0.05 and r2 = 0.62; P < 0.001, respectively) and a z score at the radius site (r2 = 0.33; P < 0.05).



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  		Figure 1. Bone densitometry measurements at the three skeletal sites according to bone histology. Data are expressed as the t score (number of SD above or below peak bone mass) and in z score (number of standard deviations above or below the mean bone mass of a control population of the same age and same sex). Each square represents one patient. The t score level classifies patients as osteoporotic (t score of -2.5 or less), osteopenic (t score of more than -2.5 and of -1 or less), or normal (t score of more than -1).

 
Dynamic study

The data are summarized in Table 4Go.


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  		Table 4. Parameters of the PTH-calcium relationships according to BFR

 
PTH secretion stimulation test (Fig. 2Go, A and B). The rate of change in serum ionized calcium was the same in the three groups. In patients with osteitis fibrosa, PTH levels reached a maximal value earlier than in the other groups and decreased slightly thereafter, whereas in patients with low and normal BFR, serum PTH levels, after reaching a maximum value, remained unchanged until the end of the test.



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  		Figure 2. Dynamic tests of parathyroid function according to bone histology. Serum ionized calcium (A) and PTH (B) levels during a 3-h infusion of EDTA and serum ionized calcium (C) and PTH (D) levels during a 3-h infusion of calcium chloride in patients with high (open squares), normal (closed circles), or low (open triangles) BFR are shown.

 
Calcium infusion test (Fig. 2Go, C and D). During the infusion of calcium chloride, serum ionized calcium levels increased from 1.25 ± 0.07 to 1.75 ± 0.16 mmol/L in patients with low bone turnover (this last value reached 1.84 ± 0.08 mmol/L in the subgroup of four patients with ABD).

The sigmoidal composite PTH-Ca2+ curves for the different groups compiled from individual curves are presented in Fig. 3Go. The slope of the curves and the calcium set-point were similar among the three groups.



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  		Figure 3. Composite ionized calcium/PTH curves according to bone histology. Ionized calcium/PTH levels (A) and ionized calcium/percentage of the maximal value of PTH achieved during hypocalcemia (B) in patients with high (open squares), normal (closed circles), or low (open triangles) BFR are shown.

 
In all dynamic studies no difference could be found between patients with normal and low BFR. Conversely, all values of PTH (basal, maximal, and minimal) were different in the three patients with high BFR, whereas the set-point and slope values did not differ.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we analyzed bone histology, bone densitometry, and dynamic PTH secretion in 16 patients with advanced renal failure who had been subjected to protein-phosphorus restriction for a mean duration of 5 yr. During the diet period, three of them biologically worsened their 2nd HPT and exhibited bone lesions of osteitis fibrosa at the time of the study, seven patients had normal bone remodeling, and six patients had low bone turnover. In this latter group, four patients displayed adynamic bone lesions with an unexpected maintenance of osteoclastic activity. More than half of the patients exhibited moderate or severe bone loss. Dynamic parathyroid function was very close in patients with normal and low BFR. In patients with high BFR, maximum PTH, minimum PTH, and basal PTH/maximum PTH were higher than in the other groups; the set-point for calcium was identical in the three groups.

The results of the present study confirm previous experimental and clinical studies showing that in advanced CRF, phosphorus restriction has a suppressive effect on PTH secretion independently of changes in calcium and calcitriol serum levels (2, 3, 5). The few patients who exhibited osteitis fibrosa had initially the highest levels of PTH and markers of bone disease. In the two other groups, there was no significant difference in initial data between patients with low and normal bone turnover.

Different factors may favor the development of ABD, which was initially related to a marked aluminum overload (31). In our ABD patients, it seems unlikely that aluminum burden played a role in view of the absence of aluminum therapy before and during the follow-up; the basal serum aluminum level was below 10 µg/L in all patients, and aluminum staining was absent on bone in all patients. The possible participation of iron load can also be eliminated with the negative stain for bone iron. Among the other potential etiological factors that may lead to defective bone formation (32), diabetes, corticosteroid treatment, hypothyroidism, and acidosis can be eliminated in our patients. Acidosis was corrected because of the low acid ash of the diet and the supplementation with calcium carbonate (33). Finally, old age is often associated with ABD (1, 5) and was a likely risk factor in our patients, although there was no statistical difference in age among the three groups, as we found a negative correlation between BFR and age (r2 = 0.24; P < 0.05). Thus, in the absence of bone biopsy before diet initiation, we cannot conclude that phosphorus restriction per se induced ABD in our four patients. However, spontaneous ABD has never been reported in uremic predialysis patients, and our patients had not taken calcium salts or calcitriol before diet initiation. Second, the major effect of a low phosphorus diet was a decrease in PTH levels, and interestingly, patients with low bone turnover had lower final PTH levels than patients with normal bone turnover. Therefore, it is possible that phosphorus-protein restriction was involved in the cause of ABD.

In our study we found that 12 patients of 16 exhibited moderate or severe bone loss at the appendicular skeletal sites. BFR explained 60% of the t score variance and 25–30% of the z score variance. In the absence of BMD measurements at the initiation of the diet, we cannot know whether our patients were already osteopenic at that time. Few studies reported BMD data for predialytic patients. Gaby et al. reported data in 11 patients suggesting that CRF could be responsible for bone loss (34).

In calcium salt-induced ABD previously reported, resorption parameters, when mentioned, were decreased (35). In our study, the most severe bone loss observed in ABD patients might be related to an uncoupling of bone cell activities characterized by a very low osteoblastic formation and a maintained osteoclastic resorption evidenced by the normal number of osteoclasts and the decrease in trabecular number (36). Two mechanisms might contribute to the maintenance of osteoclastic resorption in the absence of high PTH levels. First, it might be related to the low phosphorus intake of the patients (37). However, if none of our patients with low BFR exhibited hypophosphatemia throughout the follow-up period (not shown), there were those who significantly decreased their serum phosphate levels during the diet. Second, the low nitric oxide (NO) production observed during the VLPD, due to low L-arginine intake, might be responsible for a maintained osteoclastic resorption (38), as it has been shown that NO inhibits osteoclastic resorption in vitro and in vivo (39).

There is now some evidence in the literature that protein intake might play a role in bone mass maintenance. Protein supplementation slows bone loss in elderly osteoporosis, probably through an increase in insulin-like growth factor I (IGF-I) serum levels (40). As both energy and protein intakes are important in regulating IGF-I (41), we could hypothesize that low bone mass in our patients could be partly related to an IGF-I deficiency due to low protein intake. However, IGF-I deficiency was described in severely malnourished or undernourished patients. In our study, nutrition markers remained normal during the follow-up in all patients, caloric intake remained close to the recommended level of 30 Cal/kg·day, and no difference in weight or {Delta} weight was observed between osteoporotic patients and patients with normal bone mass.

To date, few studies have dealt with the relationship between parathyroid function, assessed by the PTH-Ca curve, and the various forms of renal osteodystrophy (42, 43, 44), but it seems that parathyroid function has not yet been evaluated in predialysis patients according to bone histology. In the present study, all patients were undergoing similar dietary and therapeutic conditions, and phosphorus levels were nearly identical in the three groups.

PTH-Ca curves show that in patients with osteitis fibrosa, maximal, minimal and basal PTH levels were higher than those observed in the other groups. The basal to maximal ratio (60%) was comparable to the values previously reported in dialysis patients with refractory hyperparathyroidism (42, 44, 45, 46), i.e. twice as high as in other patients who had values close to those observed in normal subjects.

Felsenfeld et al. (42) observed that the parathyroid response to hypocalcemic stimulation was identical in osteomalacia and ABD. In our study, this response was also very similar in patients with normal bone remodeling and those with low bone turnover. The mean basal to maximal ratio was, respectively, 29.3% and 25.4% for the two groups, i.e. close to values observed in normal subjects, confirming that in low BFR patients the secretory reserve of the parathyroids is well maintained despite low basal levels of PTH. The maximum ionized calcium level was lower in low BFR patients, suggesting a decreased sensitivity of parathyroid glands in this group compared to others.

In response to increasing serum ionized calcium, a suppressibility of parathyroid function was observed in all groups of patients regardless of their basal PTH levels. The minimal PTH level was between 5–6% of the maximal PTH level in all patients, including those with high BFR, i.e. close to that in normal individuals. It is noteworthy that during calcium infusion tests, serum ionized calcium increased more rapidly and reached higher levels at the end of the test in low BFR patients than in the other groups. These results confirm that these patients with low BFR are more sensitive to changes in calcium loading due to the decreased buffering capacity of bone for calcium. Indeed, in patients suffering from ABD developed under calcium salt therapy, the very low capacity of bone to incorporate and to buffer an extra calcium load would result in hypercalcemia, which occurs in 8–36% of the measurements in dialysis patients (47, 48), and extraosseous calcifications (49). However, in our patients, we did not observe any of these complications, probably because their total calcium intake (alimentary plus supplementation) did not exceed 1500–2000 mg/day (50).

In the present study, the calcium set-point was nearly the same whatever the form of renal osteodystrophy and was close to that of normal individuals. Thus, it does not seem that the different treatments that aim to lower PTH levels modify the set-point of calcium, as shown by Rodriguez et al. in 2nd HPT dialysis patients treated with calcitriol (51). Conversely, high phosphate concentration did not change the calcium set-point of bovine parathyroid tissue slices after a 4-h incubation (52). Indriderson et al. concluded that the existence of calcium set-point abnormalities in uremic patients with 2nd HPT of different severities did not appear to account for the excess PTH secretion (53).

Conclusion

Long term phosphorus restriction was able to control 2nd HPT in most of our patients. This treatment was not complicated with hypercalcemic episodes or extensive calcifications and therefore remains an alternative to calcitriol therapy or high doses of calcium salts in predialysis patients. Evaluation of the dynamic parathyroid function of patients exhibiting low bone turnover was similar to that of patients with normal bone turnover, except for a lower capacity to buffer a calcium load. ABD morbidity is largely unknown; however, our patients with ABD exhibited low bone mineral density associated with a maintained osteoclastic activity. Moreover, the fact that osteoporosis was also found in patients with normal bone turnover suggested that in the absence of hyper- or hypoparathyroidism, renal insufficiency and VLPD might be responsible for bone loss.

Received September 4, 1998.

Revised November 2, 1998.

Accepted November 6, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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