Bone markers in the diagnosis of low turnover osteodystrophy in haemodialysis patients
A. Fournier1,
S. Ghitu1,
G. Bako1,
L. Ben Amar1,
R. Oprisiu1,
C. Hottelart1 and
M. E. Cohen Solal2
1 Service de Néphrologie du CHU, d'Amiens
2 Unité INSERM des tissus calcifiés, Hôpital Lariboisière, Paris, France
Sir,
We are very interested in the article by Coen et al. [1] on the predictive value in patients on haemodialysis of plasma intact PTH and various bone markers for the diagnosis of adynamic bone disease and we would like to address a few comments and ask a few questions.
Comments.
This is the first paper to simultaneously assess the use of plasma intact PTH and all the presently available bone turn-over markers on a relatively large population of dialysis patients without any stainable bone aluminum for the diagnosis of adynamic bone disease. Individually, all these parameters have an excellent diagnostic specificity since it is 92.7% for PTH, 86.8% for osteocalcin, 94.8% for alkaline phosphatase, 95.10% for bone alkaline phosphatase (BALP), 93.5% for TRAP, 98.3% for ICTP and 92.7% for deoxypyridinoline. Although no significant difference is obvious among these percentages, the authors have combined all these parameters in Z score system which yielded a correct classification of only 88.9% when all the parameters, or only PTH and BALP, were included. Therefore, we quite agree with the authors that many humoral markers are supplying the same information and that determination of new bone markers does not add useful information to intact PTH and/or total alkaline phosphatase values in a haemodialysis population only mildly exposed to aluminum and without hepatic disease. Furthermore, total alkaline phosphatase is better than bone alkaline phosphatase to discriminate between adynamic bone disease from prevalent HP since the mean of total alkaline phosphatase was significantly different between patients in these groups, whereas that of BALP was not (Table 3 in [1]).
This conclusion is, however, at odds with those of Couttenye et al. [2] who stressed the superiority of BALP (measured by electrophoretic method) over intact PTH (although the Youden index was not statistically different) and with those Qi et al. [3] who stated that no definitive diagnosis between low-normal and high bone turn-over could be made on the basis of intact PTH levels between 65 and 450 pg/ml. Marked histological aluminum overload was however present in 12% and 23% of Couttenye and Qi's patients, respectively, and mainly in those with adynamic bone disease. As stressed by Coen et al. this difference in aluminum intoxication is one of the explanations why the cut off value of intact PTH for the diagnosis of adynamic bone diseases is much lower in Coen's patients than in the two other studies (80 pg/ml vs 150 and 450 pg/ml, respectively). Another reason for the difference in this cut-off value is the difference between PTH assays as alluded to by Coen et al. Lepage et al. [4] have recently shown that the INCSTAR kit used by Coen et al. gives systematically lower values of so called intact PTH than the Allegro kit of the Nichols Institute (which was used in the papers of Couttenye and Qi). The proportion of non (1-84)-intact PTH measured by these kits is lower with the INCSTAR kit than with the Allegro kit (24 vs 36%).
In 1991 we had also reported a very low cut-off for intact PTH for the diagnosis of adynamic bone disease, i.e. 40 pg/ml the upper limit of the normal range (340 pg/ml). We also explained this low value due to the lack of aluminium deposition in our patients. However, RIA used for this study was based on antibodies made by Bouillon of Leuven, which unlike the Nichols' kit do not recognize the 7-84 PTH [5]. Therefore, the greater specificity of Bouillon's RIA also explains the lower value of our cut-off value of PTH for the diagnosis of adynamic bone disease. Since 10 of our patients had true 1-84 PTH levels in the normal range with six having ABD and four `mild lesion' (i.e. normal bone formation rate plus slightly increased resorption) our data are the first to directly show that in the absence of any aluminum bone deposition and exposition to aluminum phosphate binders (as it was the case in the other series of the litterature), the uraemic state per se may induce a resistance to the remodelling effect of PTH in about 60% of dialysis patients.
Questions.
(i) We would like first to ask questions about the definition of `mixed osteodystophy'. In the methods section the authors say it is characterized by `a local increase in bone turn-over coexisting with defective mineralization'.
(ii) What are the criteria to distinguish between `local increase' and `generalized increase' in bone turn-over, a characteristic of predominant hyperparathyroid (HP) bone disease? We presume that bone turn-over was assessed by the bone formation rate measured on the whole biopsy. As shown in tables 1 and 3 of Coen's paper [1], normal bone formation rate is 0.066±0.037 µm3/µm2/die and bone formation rate of mixed osteopathy is 0.116±0.061 and that of prevalent HP is 0.566±0.412. Obviously, a significant percentage of patients with mixed osteodystrophy had a normal bone formation rate since the upper limit of normal (mean+2 SD) is 0.140.
(iii) What are the criteria for `mineralization defect', a concept included in the definition of mixed osteopathy? Coen et al. state that osteomalacia is characterized by a decrease in bone turn-over with `an increase in osteoid surface and thickness', which leads to the presumption that these two criteria were present in their group with mixed osteopathy, but not in their group with prevalent hyperparathyroid bone disease. Actually, osteoid surface (OS) and osteoid thickness (OTh) were greater in the prevalent HP group than in the mixed osteodytrophy group; 54.5 vs 27.3% for OS and 17.8 vs 12.8% for OTh. However, if the criteria of Parfitt [7] are used to describe a defect in mineralization, i.e. an abnormal increase in OTh for a given adjusted apposition rate, then the paradoxical observation of Coen et al. would be explained since this ratio is 12.8% 0.5=25.6 in the mixed osteopathy group and 17.8:1=17.8 in the prevalent HP group, whereas in the control group this ratio is 9.55:0.44=21. These data show that none of the patients in the mixed osteopathy and prevalent HP groups actually had mineralization defect. Therefore, we wonder if the `mixed osteodystrophy group' would not be more appropriately called `mild lesions' in accordance with Sherrard and Cohen Solal's criteria i.e. `normal bone formation rate+moderate increase of osteoclastic resorption' [6].
(iv) Why were the plasma concentrations of calcium and phosphate given only in table 2 and not in table 3 in which the three histological categories of patients were distinguished? It could have helped to see whether adynamic bone disease predisposes to hypercalcaemia and whether coexistence of low PTH and hypercalcaemia are synergistic for the diagnosis of this histological pattern [7]. Since adynamic bone disease may predispose to soft tissue calcifications, radiological evaluation of the latter would have been informative.
References
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Coen G, Ballanti P, Bonucci E, Calabria S, et al. Bone markers in the diagnosis of low turn over osteodystrophy in haemodialysis patients. Nephrol Dial Transplant 1998; 13: 22942302[Abstract]
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Couttennye M, d'Haese P, Van Hoof V, de Broe M. Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in hemodialysis patients. Nephrol Dial Transplant 1996; 11: 10651072[Abstract]
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Qi Q, Monier-Faugère M, Genz Z, Malluche H. Predictive value of serum PTH for bone turn over in patients on chronic maintenance dialysis. Am J Kidney Dis 1995; 26: 622631[ISI][Medline]
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Lepage R, Roy L, Brossard J et al. A non (1-84) circulation PTH fragment intervenes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998; 44: 805[Abstract/Free Full Text]
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Cohen Solal M, Serbert J, Gueris J, Bouillon R, Fournier A. Comparison of intact, mid region and carboxy terminal assays of PTH for the diagnosis of bone disease in hemodialysis patients. J Clin Endocrinol Metab 1991; 73: 516524[Abstract]
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Fournier A, Oprisiu R, Said S, Morinière P. Invasive versus non invasive diagnosis of renal bone disease. Curr Opin Nephrol Hypertens 1997; 6: 333348[ISI][Medline]
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Parfitt A. The physiologic and pathogenetic significance of bone histomorphometric data. Disorders of Bone and Mineral Metabolism. In: Coe F, ed. Raven Press, New York, 1992; 475489
Reply
Giorgio Coen,
Paola Ballanti and
Ermanno Bonucci
Renal Pathophysiology and Hypertension Unit, Institute of 2nd Clinica Medica and Department of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy
In reference to the points raised by the letter of Dr A. Fournier et al. concerning our recent article in NDT, we are glad to provide the following clarifications.
(i) As referred in the paper, the classification of different types of renal osteodystrophy was made on the basis of morphologic criteria [1]. In fact, in our opinion, the inherent variability of the histomorphometric method [2] and its scarce diagnostic sensitivity in patients without elevated increase of osteoid and/or resorption [3] make the exclusive interpretation of numerical data insufficient to correctly evaluate bone alterations in single individuals.
Based on the microscopic observation, the mixed pattern of renal osteodystrophy is defined by a spectrum of histologic features of both high turnover, hyperparathyroid bone disease and low turnover osteomalacia, which may coexist even in the same microscopic field [4]. Generally, the remodelling sites are increased in number, and these sites are heterogeneous. Active foci with wide and thick-woven osteoid seams lined by plump osteoblasts, numerous osteoclasts in enlarged Howship's lacunae, and peritrabecular fibrosis (due to hyperparathyroidism) are located adjacent to sites of thick and wide lamellar osteoid seams in contact with flat osteoblasts (typical of osteomalacia). Under UV light microscope, while double labels of tetracycline are rather numerous in correspondence of woven osteoid lined by plump osteoblasts, in adjacent sitescorresponding to lamellar osteoid seams in contact with flat osteoblaststetracycline double labels are typically reduced. In synthesis, by considering that renal osteodystrophy is characterized by a continuum of changes from high turnover to low turnover bone disease, mixed uraemic osteodystrophy includes all the transitional appearances and intermediate stages in between.
(ii) The level of bone turnover was not evaluated by the mere histomorphometric measurement of the bone formation rate, but was assessed by examining several structural and cytological characteristics of bone, as well as the pattern of the double fluorescent tetracycline labels.
In these terms, the referred local increase of bone turnover in mixed osteodystrophy means that, in contrast to prevalent hyperparathyroidism, the morphologic features typical of hyperparathyroidism were circumscribed to focalized areas of bone which alternated with zones showing typical osteomalacia features.
In bone histomorphometry, BFR/BS is measured on the whole biopsy. Thus, in the mixed type of osteodystrophy it encompasses the bone areas with increased and decreased bone turnover, expressing the average result between these two opposite processes.
(iii) On the basis of our definition of mixed osteodystrophy, the term mineralization defect indicates the osteomalacic component of such osteopathy. Thus, the authors correctly presume that the typical osteomalacic characteristics, corresponding to an increase in osteoid surface and thickness associated with a decrease in bone turnover, were present in the mixed form of osteodystrophy.
On the other hand, it is never said in the paper that an increase in osteoid surface and thickness did not occur in renal osteodystrophy with prevalent hyperparathyroid bone alterations. In fact, in this condition, as above mentioned, the increase in bone turnover is associated, among the other features, to an increase in osteoid surface and thickness. Thus, it is not surprising that the mean values of OS/BS and O.Th were greater in the group with prevalent hyperparathyroid bone disease, affected by severe hyperparathyroidism, than in the group with mixed osteodystrophy.
In reference to the criterion for the detection of a mineralization defect, based on the ratio between O.Th and Aj.AR, this ratio was slightly higher in the mixed group (25.6) and lower in the prevalent hyperparathyroidism group (17.8), in comparison with the control group (21). These data confirm that a mineralization defect do exist in the mixed osteopathy, while is not present in the prevalent hyperparathyroid bone disease. Thus, our mixed osteodystrophy group does not exactly correspond to the group with mild lesions of Sherrard and Cohen Solal defined by normal BFR/BS and increased OcS/BS.
(iv) Serum calcium and phosphate values for the three different histologic classes were not reported since they were not statistically different and did not give any contribution to differential diagnosis.
References
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Malluche H, Faugere MC. Renal Bone disease 1990: an unmet challenge for the nephrologist. Kidney Int 1990; 38: 193211[ISI][Medline]
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Bonucci E, Ballanti P, Della Rocca C, Milani S, Lo Cascio V, Imbimbo B. Technical variability of bone histomorphometric measurements. Bone Miner 1990; 11: 177186[ISI][Medline]
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Ballanti P, Della Rocca C, Bonucci E, Milani S, Lo Cascio V, Imbimbo B. Sensitivity of bone histomorphometry in the diagnosis of metabolic bone disease. Pathol Res Pract 1989; 185: 786789[ISI][Medline]
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Ballanti P. Recent advances in renal osteodystrophy. Ital J Miner Electrolyte Metab 1995; 9: 4759[ISI]