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 (3–40 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.

References

  1. 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: 2294–2302[Abstract]
  2. 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: 1065–1072[Abstract]
  3. 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: 622–631[ISI][Medline]
  4. 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]
  5. 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: 516–524[Abstract]
  6. Fournier A, Oprisiu R, Said S, Morinière P. Invasive versus non invasive diagnosis of renal bone disease. Curr Opin Nephrol Hypertens 1997; 6: 333–348[ISI][Medline]
  7. 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; 475–489

 

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.

References

  1. Malluche H, Faugere MC. Renal Bone disease 1990: an unmet challenge for the nephrologist. Kidney Int 1990; 38: 193–211[ISI][Medline]
  2. Bonucci E, Ballanti P, Della Rocca C, Milani S, Lo Cascio V, Imbimbo B. Technical variability of bone histomorphometric measurements. Bone Miner 1990; 11: 177–186[ISI][Medline]
  3. 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: 786–789[ISI][Medline]
  4. Ballanti P. Recent advances in renal osteodystrophy. Ital J Miner Electrolyte Metab 1995; 9: 47–59[ISI]




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