Clinical Study Am J Nephrol 1992; 12:419-424
Departments of Nephrology and Clinical Physiology, Hvidovre Hospital, University of Copenhagen, and Department of Pathology, Glostrup Hospital, University of Copenhagen, Denmark
Bisphosphonate Kinetics in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis: Relations to Dynamic Bone Histomorphometry, Osteocalcin and Parathyroid Hormone
Key Words
Abstract
Bone bisphosphonate clearance Bone histomorphometry Peritoneal dialysis Osteocalcin Parathyroid hormone Renal osteodystrophy
In the evaluation of renal osteodystrophy bone biopsy is often performed. However, a reliable noninvasive test could be very useful, and recently the estimation of osseous tracer uptake as an index of bone formation has been introduced - the bone bisphosphonate clearance (BBC). The aim of the present investigation therefore was to compare BBC with parameters of bone histology, serum levels of osteocalcin, alkaline phosphatase, and parathyroid hormone in patients (n = 8) undergoing continuous ambulatory peritoneal dialysis (CAPD). No significant correlations were found between BBC values and the bone histomorphometrical variables measured. A positive correlation was seen between serum osteocalcin and resorption and active resorption sur face (p < 0.05), as well as tetracycline-labelled surface, bone formation rate, surfaces, volume and tissue referents, respectively (p < 0.01). Furthermore, levels of alkaline phosphatase showed significant correlations to mineral appositional rate, tetracycline-labelled surface and bone formation rate, vol ume referent (p < 0.05). Values of parathyroid hormone were significantly correlated to resorption surface (p < 0.02), active resorption surface, mineral appositional rate and mineralization lag time (p < 0.05). In conclusion, BBC was of no use in patients treated with CAPD as a noninvasive test for evalua tion of bone histomorphometry. However, osteocalcin correlated best with resorption and bone dynamics indices. Levels of alkaline phosphatase and parathyroid hormone were of a more limited value.
Introduction
Continuous ambulatory peritoneal dialysis (CAPD) has since its introduction 16 years ago become an estab lished form of renal replacement therapy. Its use through
Received: November 22. 1991 Accepted: September 23, 1992
out the world is gradually increasing and provides a means of treating some patients with end-stage renal fail ure, who would otherwise have been denied treatment. Nearly 50,000 patients worldwide were being maintained on chronic peritoneal dialysis as of early 1990 [1], An
Preben Joffe. MD Department of Nephrology B 109 Herlcv Hospital Hcrlcv Ringvcj 75 DK-2730 Hcrlev (Denmark)
© 1992 S. Karger AG. Basel 0250-8095/92/0126-0419 $2.75/0
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Preben Joffea Lars Hyldstrupb James G. Heaj3 Jan Podenphantc Jens H. Henriksenb
Materials and Methods Patients and Controls Eight patients (6 male, 2 female) undergoing CAPD accepted to participate in the study, for which approval was obtained from the Ethics Committee for Medical Research in Copenhagen. All gave informed consent according to the principles of Helsinki declaration II. No complications or side effects were encountered. The mean age was 61 years (range 35-84). Patients had been treated with CAPD for an average of 28 months (range 2-92). All but 1 patient were still excreting urine. Patients' mean weight on the day of the study was 67.0 kg (range 40.0-82.1). CAPD was performed by the standard technique using 3 or 4 dialysis bag exchanges per day. None had clin ical signs or symptoms of peritonitis for at least 2 months preceding the actual investigations, and no patients showed signs of liver dis ease or disorders affecting extraosseous collagen turnover. No pa tients were treated with vitamin D? analogues.
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Principles and Mathematical Models The normal range for BBC was adapted from our laboratory, where BBC was found within the range of 54.5-104.6 ml/min in 7 subjects without bone disease [7], The BBC data were converted into ml/min/60 kg body weight (BW) before statistical analysis was per formed. The technique used is based on the parallel determination of the total plasma clearances of 99mTc-methylene bisphosphonate ("T c -M B P ) and 5lCr-cthylencdiaminetetraacetic acid (5lCrEDTA) using constant infusions of tracers [7]. Using Stewart’s prin ciple, the whole body plasma clearance at steady state (Clpi) is given by the equation:
C lp ,-^ -
(I)
''-pKoo)
where J m and Cpi^i are the infusion rates and the plasma activity at steady state, respectively. Since the plasma clearance of 99mTc-MBP (Clpi. mbp) equals the sum of bone, peritoneal and renal 99mTc-MBP clearances, the Clpi, mbp can be expressed as: Clpi.MBP = CIpcr.MBP + Clbonc.MBP + Clkid. MBP
(H )
where Clpcr. mbp- CLb0nc. mbp and Clkid. mbp are plasma clearances over the peritoneal membrane, and in bone and kidney, respectively. As the sum of Clpcr, mbp and Clkid. mbp equals the total plasma clearance of 5lCr-EDTA [7], the Clbonc.MBP is given as: Clbone, MBP = Clpt.MBP - Clp,.Cr-EDTA
(III)
Inserted in Equation (I) the BBC is given as: C lb o n e =
Jin.MBP
Jin. Cr-EDTA
Cp|(oo). MBP
Cpl(oo), Cr-EDTA
(IV)
Study Design Prior to the start of the investigation, the preceding dialysis exchange was completely drained from the peritoneal cavity over a period of 30 min with the patient in a sitting position. Thereafter, each patient performed a new dialysis fluid exchange using a glucose concentration of 13.6mg/dl (Dianeal, Baxter Healthcare Corpora tion). In patients still excreting urine, the urinary bladder was emp tied. All patients were then weighed. Before administration of " T c MBP and 5lCr-EDTA. an intravenous cannula was inserted into a forearm vein. Blood samples were collected from the opposite arm after 5 ml of blood was removed before each sample for counting was drawn. The samples used for measurements were immediately cen trifuged. A constant infusion (calibrated Dich pump, Denmark) of 99mTc-MBP and 51Cr-EDTA was started after intravenous bolus injection of 130 MBq (3.5 mCi) 99mTc-MBP and 3.9 MBq (105 pCi) 5lCr-EDTA simultaneously with inflow of a new dialysis bag. The total dosages of 99mTc-MBP and -MCr-EDTA were 185 MBq (5.0 pCi) and 5.55 MBq (150 pCi). respectively. A sample of dialysate (5 ml) and blood was obtained prior to infusion and subsequent blood sam ples (5 ml) were taken after 0, 5, 15, 30 min and 1, 1.5, 2, 2.5, 3. 3.5 and 4 h. The dialysis cycle was terminated at 4 h, after which the dialysate was completely drained, measured and sampled for count ing. Also urine was collected, measured and sampled for counting. Investigations Serum alkaline phosphatase acitvity was measured by standard method, in accordance with the recommended Scandinavian stan dard [10] (SMAC, Technicon Instruments Corporation, Tarrytown, N.Y., USA). Total calcium was determined by standard methods
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Bone Bisphosphonate and CAPD
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almost inevitable consequence of chronic renal failure is the development of renal osteodystrophy [2, 3], Biochem ical abnormalities characterizing this uremic complica tion are increased serum levels of phosphate and parathy roid hormone and decreased concentration of calcium and 1,25-dihydroxycholecalciferol [4, 5]. Despite reason able control of serum calcium and phosphate levels dur ing CAPD [5], these patients also suffer from varying degrees of renal osteodystrophy [6], Although histomorphometric evaluation of bone biopsies is till considered the most reliable method for establishing the diagnosis of renal osteodystrophy [2, 6], a noninvasive test for the evaluation of bone metabolism is needed. Recently the estimation of osseous tracer uptake as an index of bone formation has been reported - the bone bisphosphonate clearance (BBC) [7], This method is based on the high affinity of bisphosphonates for bone regions with in creased metabolic activity, as known from bone scintigra phy [8]. At the same time, serum levels of osteocalcin have been found to correlate with histomorphometric indices of bone formation [9], We decided to evaluate the BBC tracer technique as well as serum osteocalcin mea surements in patients undergoing CAPD, with respect to quantification of renal osteodystrophy. The aim of the present investigation was therefore to (1) apply the BBC technique, which allows estimation of bisphosphonate uptake in bone in patients receiving CAPD: (2) compare BBC with parameters of bone histology, and (3) evaluate measurements of alkaline phosphatase, osteocalcin, and parathyroid hormone (PTH) as diagnostic tools in rela tion to BBC and bone histomorphometry.
Table 1. Bone histomorphometric definitions and variables Definitions and calculations
Variables Resorption
length of scalloped surface w ^^ n/ trabecular bone perimeter
Resorption surface Active resorption surface (osteoclast surface)
length of osteoclast covered surface w ^ trabecular bone perimeter
Osteoid Mean osteoid seam width (OSW)
jim
Osteoid surfaces (OS)
osteoid covered surface w --------------------------------- X 100% trabecular bone perimeter OSW X osteoid covered surface
Osteoid volume
areas of trabecular bone
Bone dynamics Mineral appositional rate (MAR) Tetracycline-labelled surfaces (LS)
X 100%
distance between tetracycline labels , ,, , ---------------------------------------------- (gm/dav) marker interval length of double-labelled surface + 0.5 X length of single-labelled surface (mm)
Corrected apposition rate [M(f)]
MAR X LS , , qs (gm/day)
Mineralization lag time
0SW ---— 1A (days)* M(0
Bone formation rate (surface)
MAR X LS X 365 „ Jt , „ „ --------------------------------- X — (pmvpm-/years) trabecular bone perimeter 4
Bone formation rate (volume)
MAR X LS X 36.5 /n, , ----------------------------- (%/year) area of trabecular bone
Bone formation rate (tissue)
MAR X LS X 36.5 , . ------------------------------ (%/year) area of trabecular tissue
Iliac Crest Biopsies Transcortical biopsies were obtained under local anesthesia and intravenous sedation 2 cm behind and another 2 cm below the left or right anterior superior part o f the iliac crest using a Bordier trephine of 8 mm internal diameter. Prior intravital tetracycline double-labelling with oral tetracycline chloride (250 mg 3 times a day) and demeclocycline hydrochloride (300 mg 3 times a day) was given for two 2-day periods, separated by an interval of 11 days. The biopsies were obtained 3-4 days after the last oral dosis of demeclocycline hydro chloride. The bone biopsies underwent extensive structural and his tomorphometric analyses, including staining for aluminum. The methods and the diagnostic criteria used have been described in detail previously [3,6, 12-14], The bone histomorphometric calcula tions, definitions and indices used are given in table 1. Based on these analyses and calculations the bone biopsies could be subdi vided into 6 diagnostic groups: ( I) osteitis fibrosa; (2) osteomalacia; (3) aplastic lesion; (4) osteopenia; (5) mixed uremic osteodystrophy, and (6) normal.
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(SMAC. Technicon Instruments Corporation. Tarrytown, N.Y., USA). Ionized calcium was analyzed at pH = 7.4 using an ionized calcium analyzer (1CA1, Radiometer, Copenhagen, Denmark). De termination of intact PTH/.S 4 was performed using the Allegro intact PTH kit (Nicols Institute Diagnostics, San Juan Capistrano, Calif., USA). The system has a sensitivity of 1 pg/ml of PTH|_g4 . and is highly specific for only the biologically active and intact PTH mole cule. Normal range, intra- and interassay variation is I. I -4.8 pmol/1, 1.8 and 5.6% within the normal range, respectively. Serum osteocal cin was determined by solid-phase enzyme-linked immunosorbent assay (ELISA). This competitive assay is based on biotinylization of osteocalcin with secondary binding to avidin-labelled peroxidase. The detection limit is < 0 .5 gg/1, and the total precision error is 7.9% for osteocalcin concentrations within the normal range. This ELISA had a normal range of 2.1-12.1 gg/1 [11]. Counting. All portions of blood, dialysate and urine were counted in a well type gamma scintillation counter (Compugamma, LK.B Wallac). At least 10,000 counts were recorded.
Table 2. Biochemical and histomorphometric indices of bone metabolism with ranking of measured parameters in the 8 patients according to BBC-values Pt. No.
1 2 3 4 5 6 7 8
D iagnosis o f bo n e biopsies
Osteitis fibrosa Osteomalacia Aplastic lesion Osteitis fibrosa Normal Normal Osteitis fibrosa Osteitis fibrosa
BBC
O steocalcin
PT H
Phosphate
gg/1
A lkaline phosphatase U /l
pm ol/l
mmol/1
T otal calcium m m ol/l
m l/m in
C a^
7 1 .2
4 0 .4
324
4 6 .9
1 .6 2
2 .1 5
_
7 3 .4
4 .5
126
7 .8
1 .0 3
1 .9 6
1 .0 8
8 4 .5
9 .5
2 31
1 6 .8
1 .8 5
2 .3 3
1 .2 2
8 7 .6
2 9 .0
400
2 5 .5
3 .1 9
2 .3 3
1 .0 5
9 5 .0
1 3 .4
273
1 2 .6
1 .9 7
2 .2 4
1 1 1 .1
3 .0
262
3 1 .2
2 .0 0
2 .4 0
mmol/1
1 .1 9 -
1 2 2 .3
1 4 .4
315
3 4 .9
2 .1 6
1 .8 5
1 .0 4
1 4 7 .5
4 3 .3
447
2 7 .6
1 .6 5
2 .2 0
1 .0 8
Median Range
1 3 .9
294
2 6 .6
1.91
2 .2 2
1 .0 8
7 1 .2 - 1 4 7 .5
3 .0 - 4 3 .3
1 2 6 -4 4 7
7 .8 - 4 6 .9
1 .0 3 - 3 .1 9
1 .8 5 - 2 .4 0
1 .0 4 - 1 .2 2
Normal range
5 4 .0 - 1 0 4 .6
7 .1 - 1 2 .1
8 0 -2 7 5
1 .1 - 4 .8
0 .7 8 - 1 .5 1
2 .1 7 - 2 .5 7
1 .1 5 - 1 .3 1
9 1 .3
Serum levels of osteocalcin, alkaline phosphatase, PTH, phosphate, total calcium and ionized calcium are shown as well. Patient No. 2 had histochemical aluminum deposition on the mineralization front.
Results
In table 2, diagnosis of bone histomorphometry, mea surements of BBC and serum levels of osteocalcin, alka line phosphatase, PTH, phosphate, total calcium and ion ized calcium are given with ranking of the patients according to BBC values. Median value of BBC was found to be 91.3 ml/min/60 kg BW (range 71.2-147.5). As mentioned earlier, the plasma clearance of 99mTc-MBP consisted of the sum of the bone, peritoneal and renal 99mTc-MBP clearances. We found that the peritoneal clearance of 99mTc-MBP (Clpcr.MBp) constituted in median 5.1% (range 3.5-8.8) of the plasma clearance of 99mTcMBP whereas the median renal 99mTc-MBP clearance (Clkki.MBp) accounted for 2.3% (range 1.2-5.2). The sums of Clpcr.MBP and Clkid.MBP were not statistically signifi cantly different from the total plasma clearance of 5lCrEDTA. Five patients had BBC values within the normal range, even though 4 of these patients had abnormal bone histo morphometry (table 2). The highest values of BBC were found in 2 patients with osteitis fibrosa, while 2 other
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patients with the same histomorphometric diagnosis had values of BBC within the normal range (table 2). Altogeth er, no relations between BBC values and the diagnosis of bone biopsies were found. The highest values of osteocal cin, alkaline phosphatase, and PTH were found in pa tients suffering from osteitis fibrosa. In table 3, indices of bone resorption and formation are given as well as addi tional histomorphometrical profiles of investigated pa tients. Table 4 shows coefficients of correlation for some of the most relevant bone indices and the relation to the noninvasive markers of bone metabolism evaluated. No significant correlations were found between BBC values and any of the bone histomorphometric variables mea sured. A positive correlation was seen between serum lev els of osteocalcin and resorption and active resorption surface (p < 0.05), as well as tetracycline labelled surface, bone formation rate, surfaces, volume and tissue referents (p < 0.01). Furthermore, levels of alkaline phosphatase showed significant correlations to mineral appositional rate, tetracycline labelled surface, and bone formation rate, volume referent (p < 0.05). PTH were found to cor relate significantly to resorption surface (p < 0.02) and to active resorption surface, mineral appositional rate and corrected apposition rate (p < 0.05).
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Statistical Evaluations Data are presented as mean ± standard deviation and median and range when appropriate. Statistical evaluation was performed by linear regression analysis. Differences were considered significant when p < 0.05.
Table 3. Histomorphometrical profile of investigated patients (No. 1-8)
Pt. No.
RS, %
ARS. %
OS.%
OV,%
MAR pm/day
LS mm
M(f) pm/day
BFRS BFRV pm 3/pm 2/yr %/yr
1 2 3 4 5 6 7 8
5.2 1.4 0.9 3.0 2.3 1.4 4.6 3.2
0.92 0.37 0.16 0.95 0.38 0.35 0.90 0.71
29.2 43.4 15.1 30.5 13.5 6.8 10.8 24.3
6.0 9.2 2.1 5.8 1.5 0.8 1.8 5.1
1.1 0.0 0.0 0.9 0.9 1.0 0.8 1.0
13.0 0.0 0.0 3.5 3.5 0.9 5.3 26.3
0.5 0.0 0.0 0.1 0.3 0.4 0.4 0.6
39.6 0.0 0.0 6.4 11.2 6.9 13.7 41.5
67.4 0.0 0.0 13.5 17.4 12.6 27.5 91.8
18.9 0.0 0.0 2.6 3.9 2.2 4.0 16.2
Mean ± SD
2.8 1.6
0.59 0.31
21.7 12.3
4.0 2.9
0.7 0.5
6.6 9.0
0.3 0.2
14.9 16.5
28.8 33.3
6.0 7.3
BFR, %/yr
RS = Resorption surface: ARS = active resorption surface: OS = osteoid surface: OV = osteoid volume; MAR = mineral appositional rate; LS = tetracycline-labelled surface; M(f) = corrected apposition rate; BFRS v , = bone forma tion rate, surfaces, volume and tissue referents, respectively.
The 24-hour whole body retention of bisphosphonate (WBR) was introduced in 1978 and has since then been used as a noninvasive measure of bone metabolism [7], However, WBR has one major drawback, namely its dependency of renal function. This was avoided when Hyldstrup et al. [7] described a method allowing an esti mation of osseous tracer uptake independent of the renal function (the BBC), which allows investigation of bone metabolism in patients undergoing dialysis. This noncompartmental model is based on the use of 51Cr-EDTA as a cotracer and requires that renal and other nonosseous clearances of 99mTc-MBP and 5lCr-EDTA are similar [7], In the present study the model has been further adapted to CAPD so that the clearance of 99mTc-MBP from plasma constitutes not only the sum of bone and renal clearances but the peritoneal clearances of 99mTc-MBP as well. This is based on the assumption that both substances are cleared from plasma by glomerular filtration, and diffusion/filtration takes place into the extravascular space, including peritoneal fluid, while only MBP is taken up by bone in regions of increased bone turnover [7], Limited data are available on BBC as a radionuclide method for assessment of renal osteodystrophy. Gruenewald et al. [15] compared the 51Cr-EDTA/99mTc-MBP ratio in 44 patients undergoing hemodialysis and in 13 on CAPD against serum calcium, phosphate, alkaline phos phatase, PTH, bone scan images, forearm bone density as well as radiology. Thirty-nine hemodialysis patients and 8
Table 4. Coefficient o f correlation between histomorphometric variables. BBC and serum levels of osteocalcin, alkaline phosphatase and PTH
Variables
BBC
Osteocalcin
Alkaline PTH phosphatase
Resorption RS ARS
0.14 0.17
0.69* 0.71*
0.56 0.68
Osteoid OS OV Bone dynamics MAR LS M(0 BFRS BFRV BFR,
-0.46 -0.38 0.42 0.59 0.64 0.39 0.51 0.24
0.29 0.32 0.57 0.86*** 0.58 0.87*** 0.87*** 0.88***
-0.15 -0.11 0.73* 0.74* 0.62 0.66 0.71* 0.60
0.78** 0.69* -0.22 -0.14 0.69* 0.43 0.70* 0.65 0.59 0.67
See table 3 for abbreviations. * p < 0.05: ** p < 0.02; *** p < 0.01.
patients undergoing CAPD had a second study performed approximately 1 year later. In the initial study, 93% had abnormal isotope ratios of 51Cr-EDTA/99mTc-MBP with a poor correlation between this ratio and bone density. In a later study, they found agreements about the direction of changes between serum alkaline phosphatase and 5lCrEDTA/99mTc-MBP ratio in 81 %, but in 39% of these 81 %
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Discussion
the serum levels of alkaline phosphatase remained within the normal range. Based on this study the authors con cluded that the 5lCr-EDTA/99mTc-MBP ratio is a simple test of quantifying bone uptake of MBP for assessment and follow-up of renal osteodystrophy. Neither bone biopsies nor the serum levels of osteocalcin were per formed. BBC values were converted into ml/min/60 kg body weight before analysis of correlations to serum levels of alkaline phosphatase, osteocalcin and PTH were per formed (table 4). This was done as variations in bone mass are likely to influence bone clearance of MBP. The main observation in this study is the lack of correlation between BBC and bone histomorphometry as well as between BBC and the diagnosis of bone biopsies. How ever, serum levels of osteocalcin gave more information of the bone variables than the more time consuming BBC test and are of some use for evaluation of bone resorption and dynamics in patients undergoing CAPD as a noninvasive parameter. Serum levels of alkaline phosphatase and PTH gave less information of bone metabolism in the investigated dialysis patients, although some significant correlations were found. No single explanation of these results appears. However, it is reasonable to believe that differences in the sensitivity of the various markers could be of significance. Moreover, there is every probability
that the investigated formation markers represent various aspects of the osteoblast function [ 14], Four of our 8 patients, having had a bone biopsy show ing osteitis fibrosa, had elevated serum alkaline phospha tase. The elevations in the levels of alkaline phosphatase were reflected in individual values of osteocalcin and PTH. This is contrary to our previous findings that CAPD per se removes nearly no alkaline phosphatase but substantial amounts of PTH [5]. In conclusion, the present study has emphasized that the BBC technique can be used independently of renal function in patients treated with CAPD but gives no information on bone histomorphometry or diagnoses of bone disease in these patients. Serum osteocalcin corre lated best with resorption and bone dynamics indices. Levels of alkaline phosphatase and PTH were, however, of more limited value. Acknowledgements We wish to thank technician-in-chief Ingelise Siegumfeldt and technician Janne Berg for their enthusiastic and careful assistance during the tracer part of the study. Osteocalcin measurements were performed due to grants from the Danish Rheumatism Association. P.J. was supported in part by grants from the Foundation of Else & Mogens Weddell-Wedellsborg and the Danish Rheumatism Associa tion.
1 Nolph KD: Overview of peritoneal dialysis 1991 (handout). I Ith Annu Conf Periton Dial 1991. p 1. 2 Heaf JG. Joffe P. Podenphant J. Andersen JR: Non-invasive diagnosis of uremic osteodystro phy: Uses and limitations. Am J Nephrol 1987; 7:203-211. 3 Heaf JG, Podenphant J. Joffe P, Andersen JR. Fugleberg S, Braendstrup O: The effect of oral aluminium salts on the bone of non-dialysed uremic patients. Scand J Urol Nephrol 1987: 21:229-233. 4 Joffe P, Heaf JG: Vitamin D and vitamin Dbinding protein kinetics in patients treated with continuous ambulatory peritoneal dialy sis. Periton Dial Int 1989:9:281-284. 5 Joffe P, Heaf JG: The effect of continuous ambulatory peritoneal dialysis on biochemical products related to renal osteodystrophy. Trace Elem Med 1989:6(4):169-172. 6 Joffe P. Podenphant J, Heaf JG: Bone histol ogy in CAPD patients: A comparison with hemodialysis and conservatively treated chronic urémies; in Khanna R, et al (eds): Advances in Peritoneal Dialysis 1989. Toron to, Périt Dial Bull, 1989. pp 171-176.
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7 Hyldstrup L. McNair P. Ring P. Henriksen O: Studies on diphosphonate kinetics. II. Whole body uptake rate during constant infusion - a refined index of bone metabolism. Eur J Nucl Med 1987;12:581-584. 8 Mosekilde L, Hasling C. Charles P. Tigehoj Jensen F: Bisphosphonate whole body reten tion test: Relations to bone mineralization rate, renal function and bone mineral content in osteoporosis and metabolic bone disorders. Eur J Clin Invest 1987; 17:530-537. 9 Brown JP. Delnas P, Malaval C, Edouard MG. Meunicr PJ: Serum bone GLA-protein: A spe cific marker of bone formation in post-meno pausal osteoporosis. Lancet 1984;i: 1091 — 1093. 10 Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology: Recommended methods for deter mination of four enzymes in blood. Scand J Clin Lab Invest 1974;33:281-306.
11 Hyldstrup L, Clemmensen I, Jensen BA, Transbol I: Non-invasive evaluation of bone forma tion: Measurements of serum alkaline phos phatase, whole body retention of diphospho nate and serum osteocalcin in metabolic bone disorders and thyroid disease. Scand J Clin Lab Invest 1988:48:611-619. 12 Joffe P. Olsen F. Heaf JG, Gammelgaard B. Podenphant J: Aluminium concentration in se rum. dialysate. urine and bone among patients undergoing CAPD. Clin Nephrol 1989:5:133— 138. 13 Podenphant J, Heaf JG, Joffe P: Metabolic bone disease and aluminium contamination in 38 uremic patients. Acta Pathol Microbiol Im munol Scand 1986;94:1-6. 14 Podenphant J, Johansen JS. Thomsen K, Riis BJ. Leth A, Christiansen C: Bone turnover in spinal osteoporosis. J Bone Miner Res 1987:6: 497-503. 15 Gruenewald SM, Fawdry RM. Farlow DC, Steward JH: CrEDTA/TcMDP ratio - a new radionuclide method for assessment of renal osteodystrophy (abstract). Kidney Int 1988:33: 139-140.
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References
Departments of Nephrology and Clinical Physiology, Hvidovre Hospital, University of Copenhagen, and Department of Pathology, Glostrup Hospital, University of Copenhagen, Denmark
Bisphosphonate Kinetics in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis: Relations to Dynamic Bone Histomorphometry, Osteocalcin and Parathyroid Hormone
Key Words
Abstract
Bone bisphosphonate clearance Bone histomorphometry Peritoneal dialysis Osteocalcin Parathyroid hormone Renal osteodystrophy
In the evaluation of renal osteodystrophy bone biopsy is often performed. However, a reliable noninvasive test could be very useful, and recently the estimation of osseous tracer uptake as an index of bone formation has been introduced - the bone bisphosphonate clearance (BBC). The aim of the present investigation therefore was to compare BBC with parameters of bone histology, serum levels of osteocalcin, alkaline phosphatase, and parathyroid hormone in patients (n = 8) undergoing continuous ambulatory peritoneal dialysis (CAPD). No significant correlations were found between BBC values and the bone histomorphometrical variables measured. A positive correlation was seen between serum osteocalcin and resorption and active resorption sur face (p < 0.05), as well as tetracycline-labelled surface, bone formation rate, surfaces, volume and tissue referents, respectively (p < 0.01). Furthermore, levels of alkaline phosphatase showed significant correlations to mineral appositional rate, tetracycline-labelled surface and bone formation rate, vol ume referent (p < 0.05). Values of parathyroid hormone were significantly correlated to resorption surface (p < 0.02), active resorption surface, mineral appositional rate and mineralization lag time (p < 0.05). In conclusion, BBC was of no use in patients treated with CAPD as a noninvasive test for evalua tion of bone histomorphometry. However, osteocalcin correlated best with resorption and bone dynamics indices. Levels of alkaline phosphatase and parathyroid hormone were of a more limited value.
Introduction
Continuous ambulatory peritoneal dialysis (CAPD) has since its introduction 16 years ago become an estab lished form of renal replacement therapy. Its use through
Received: November 22. 1991 Accepted: September 23, 1992
out the world is gradually increasing and provides a means of treating some patients with end-stage renal fail ure, who would otherwise have been denied treatment. Nearly 50,000 patients worldwide were being maintained on chronic peritoneal dialysis as of early 1990 [1], An
Preben Joffe. MD Department of Nephrology B 109 Herlcv Hospital Hcrlcv Ringvcj 75 DK-2730 Hcrlev (Denmark)
© 1992 S. Karger AG. Basel 0250-8095/92/0126-0419 $2.75/0
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Preben Joffea Lars Hyldstrupb James G. Heaj3 Jan Podenphantc Jens H. Henriksenb
Materials and Methods Patients and Controls Eight patients (6 male, 2 female) undergoing CAPD accepted to participate in the study, for which approval was obtained from the Ethics Committee for Medical Research in Copenhagen. All gave informed consent according to the principles of Helsinki declaration II. No complications or side effects were encountered. The mean age was 61 years (range 35-84). Patients had been treated with CAPD for an average of 28 months (range 2-92). All but 1 patient were still excreting urine. Patients' mean weight on the day of the study was 67.0 kg (range 40.0-82.1). CAPD was performed by the standard technique using 3 or 4 dialysis bag exchanges per day. None had clin ical signs or symptoms of peritonitis for at least 2 months preceding the actual investigations, and no patients showed signs of liver dis ease or disorders affecting extraosseous collagen turnover. No pa tients were treated with vitamin D? analogues.
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Principles and Mathematical Models The normal range for BBC was adapted from our laboratory, where BBC was found within the range of 54.5-104.6 ml/min in 7 subjects without bone disease [7], The BBC data were converted into ml/min/60 kg body weight (BW) before statistical analysis was per formed. The technique used is based on the parallel determination of the total plasma clearances of 99mTc-methylene bisphosphonate ("T c -M B P ) and 5lCr-cthylencdiaminetetraacetic acid (5lCrEDTA) using constant infusions of tracers [7]. Using Stewart’s prin ciple, the whole body plasma clearance at steady state (Clpi) is given by the equation:
C lp ,-^ -
(I)
''-pKoo)
where J m and Cpi^i are the infusion rates and the plasma activity at steady state, respectively. Since the plasma clearance of 99mTc-MBP (Clpi. mbp) equals the sum of bone, peritoneal and renal 99mTc-MBP clearances, the Clpi, mbp can be expressed as: Clpi.MBP = CIpcr.MBP + Clbonc.MBP + Clkid. MBP
(H )
where Clpcr. mbp- CLb0nc. mbp and Clkid. mbp are plasma clearances over the peritoneal membrane, and in bone and kidney, respectively. As the sum of Clpcr, mbp and Clkid. mbp equals the total plasma clearance of 5lCr-EDTA [7], the Clbonc.MBP is given as: Clbone, MBP = Clpt.MBP - Clp,.Cr-EDTA
(III)
Inserted in Equation (I) the BBC is given as: C lb o n e =
Jin.MBP
Jin. Cr-EDTA
Cp|(oo). MBP
Cpl(oo), Cr-EDTA
(IV)
Study Design Prior to the start of the investigation, the preceding dialysis exchange was completely drained from the peritoneal cavity over a period of 30 min with the patient in a sitting position. Thereafter, each patient performed a new dialysis fluid exchange using a glucose concentration of 13.6mg/dl (Dianeal, Baxter Healthcare Corpora tion). In patients still excreting urine, the urinary bladder was emp tied. All patients were then weighed. Before administration of " T c MBP and 5lCr-EDTA. an intravenous cannula was inserted into a forearm vein. Blood samples were collected from the opposite arm after 5 ml of blood was removed before each sample for counting was drawn. The samples used for measurements were immediately cen trifuged. A constant infusion (calibrated Dich pump, Denmark) of 99mTc-MBP and 51Cr-EDTA was started after intravenous bolus injection of 130 MBq (3.5 mCi) 99mTc-MBP and 3.9 MBq (105 pCi) 5lCr-EDTA simultaneously with inflow of a new dialysis bag. The total dosages of 99mTc-MBP and -MCr-EDTA were 185 MBq (5.0 pCi) and 5.55 MBq (150 pCi). respectively. A sample of dialysate (5 ml) and blood was obtained prior to infusion and subsequent blood sam ples (5 ml) were taken after 0, 5, 15, 30 min and 1, 1.5, 2, 2.5, 3. 3.5 and 4 h. The dialysis cycle was terminated at 4 h, after which the dialysate was completely drained, measured and sampled for count ing. Also urine was collected, measured and sampled for counting. Investigations Serum alkaline phosphatase acitvity was measured by standard method, in accordance with the recommended Scandinavian stan dard [10] (SMAC, Technicon Instruments Corporation, Tarrytown, N.Y., USA). Total calcium was determined by standard methods
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almost inevitable consequence of chronic renal failure is the development of renal osteodystrophy [2, 3], Biochem ical abnormalities characterizing this uremic complica tion are increased serum levels of phosphate and parathy roid hormone and decreased concentration of calcium and 1,25-dihydroxycholecalciferol [4, 5]. Despite reason able control of serum calcium and phosphate levels dur ing CAPD [5], these patients also suffer from varying degrees of renal osteodystrophy [6], Although histomorphometric evaluation of bone biopsies is till considered the most reliable method for establishing the diagnosis of renal osteodystrophy [2, 6], a noninvasive test for the evaluation of bone metabolism is needed. Recently the estimation of osseous tracer uptake as an index of bone formation has been reported - the bone bisphosphonate clearance (BBC) [7], This method is based on the high affinity of bisphosphonates for bone regions with in creased metabolic activity, as known from bone scintigra phy [8]. At the same time, serum levels of osteocalcin have been found to correlate with histomorphometric indices of bone formation [9], We decided to evaluate the BBC tracer technique as well as serum osteocalcin mea surements in patients undergoing CAPD, with respect to quantification of renal osteodystrophy. The aim of the present investigation was therefore to (1) apply the BBC technique, which allows estimation of bisphosphonate uptake in bone in patients receiving CAPD: (2) compare BBC with parameters of bone histology, and (3) evaluate measurements of alkaline phosphatase, osteocalcin, and parathyroid hormone (PTH) as diagnostic tools in rela tion to BBC and bone histomorphometry.
Table 1. Bone histomorphometric definitions and variables Definitions and calculations
Variables Resorption
length of scalloped surface w ^^ n/ trabecular bone perimeter
Resorption surface Active resorption surface (osteoclast surface)
length of osteoclast covered surface w ^ trabecular bone perimeter
Osteoid Mean osteoid seam width (OSW)
jim
Osteoid surfaces (OS)
osteoid covered surface w --------------------------------- X 100% trabecular bone perimeter OSW X osteoid covered surface
Osteoid volume
areas of trabecular bone
Bone dynamics Mineral appositional rate (MAR) Tetracycline-labelled surfaces (LS)
X 100%
distance between tetracycline labels , ,, , ---------------------------------------------- (gm/dav) marker interval length of double-labelled surface + 0.5 X length of single-labelled surface (mm)
Corrected apposition rate [M(f)]
MAR X LS , , qs (gm/day)
Mineralization lag time
0SW ---— 1A (days)* M(0
Bone formation rate (surface)
MAR X LS X 365 „ Jt , „ „ --------------------------------- X — (pmvpm-/years) trabecular bone perimeter 4
Bone formation rate (volume)
MAR X LS X 36.5 /n, , ----------------------------- (%/year) area of trabecular bone
Bone formation rate (tissue)
MAR X LS X 36.5 , . ------------------------------ (%/year) area of trabecular tissue
Iliac Crest Biopsies Transcortical biopsies were obtained under local anesthesia and intravenous sedation 2 cm behind and another 2 cm below the left or right anterior superior part o f the iliac crest using a Bordier trephine of 8 mm internal diameter. Prior intravital tetracycline double-labelling with oral tetracycline chloride (250 mg 3 times a day) and demeclocycline hydrochloride (300 mg 3 times a day) was given for two 2-day periods, separated by an interval of 11 days. The biopsies were obtained 3-4 days after the last oral dosis of demeclocycline hydro chloride. The bone biopsies underwent extensive structural and his tomorphometric analyses, including staining for aluminum. The methods and the diagnostic criteria used have been described in detail previously [3,6, 12-14], The bone histomorphometric calcula tions, definitions and indices used are given in table 1. Based on these analyses and calculations the bone biopsies could be subdi vided into 6 diagnostic groups: ( I) osteitis fibrosa; (2) osteomalacia; (3) aplastic lesion; (4) osteopenia; (5) mixed uremic osteodystrophy, and (6) normal.
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(SMAC. Technicon Instruments Corporation. Tarrytown, N.Y., USA). Ionized calcium was analyzed at pH = 7.4 using an ionized calcium analyzer (1CA1, Radiometer, Copenhagen, Denmark). De termination of intact PTH/.S 4 was performed using the Allegro intact PTH kit (Nicols Institute Diagnostics, San Juan Capistrano, Calif., USA). The system has a sensitivity of 1 pg/ml of PTH|_g4 . and is highly specific for only the biologically active and intact PTH mole cule. Normal range, intra- and interassay variation is I. I -4.8 pmol/1, 1.8 and 5.6% within the normal range, respectively. Serum osteocal cin was determined by solid-phase enzyme-linked immunosorbent assay (ELISA). This competitive assay is based on biotinylization of osteocalcin with secondary binding to avidin-labelled peroxidase. The detection limit is < 0 .5 gg/1, and the total precision error is 7.9% for osteocalcin concentrations within the normal range. This ELISA had a normal range of 2.1-12.1 gg/1 [11]. Counting. All portions of blood, dialysate and urine were counted in a well type gamma scintillation counter (Compugamma, LK.B Wallac). At least 10,000 counts were recorded.
Table 2. Biochemical and histomorphometric indices of bone metabolism with ranking of measured parameters in the 8 patients according to BBC-values Pt. No.
1 2 3 4 5 6 7 8
D iagnosis o f bo n e biopsies
Osteitis fibrosa Osteomalacia Aplastic lesion Osteitis fibrosa Normal Normal Osteitis fibrosa Osteitis fibrosa
BBC
O steocalcin
PT H
Phosphate
gg/1
A lkaline phosphatase U /l
pm ol/l
mmol/1
T otal calcium m m ol/l
m l/m in
C a^
7 1 .2
4 0 .4
324
4 6 .9
1 .6 2
2 .1 5
_
7 3 .4
4 .5
126
7 .8
1 .0 3
1 .9 6
1 .0 8
8 4 .5
9 .5
2 31
1 6 .8
1 .8 5
2 .3 3
1 .2 2
8 7 .6
2 9 .0
400
2 5 .5
3 .1 9
2 .3 3
1 .0 5
9 5 .0
1 3 .4
273
1 2 .6
1 .9 7
2 .2 4
1 1 1 .1
3 .0
262
3 1 .2
2 .0 0
2 .4 0
mmol/1
1 .1 9 -
1 2 2 .3
1 4 .4
315
3 4 .9
2 .1 6
1 .8 5
1 .0 4
1 4 7 .5
4 3 .3
447
2 7 .6
1 .6 5
2 .2 0
1 .0 8
Median Range
1 3 .9
294
2 6 .6
1.91
2 .2 2
1 .0 8
7 1 .2 - 1 4 7 .5
3 .0 - 4 3 .3
1 2 6 -4 4 7
7 .8 - 4 6 .9
1 .0 3 - 3 .1 9
1 .8 5 - 2 .4 0
1 .0 4 - 1 .2 2
Normal range
5 4 .0 - 1 0 4 .6
7 .1 - 1 2 .1
8 0 -2 7 5
1 .1 - 4 .8
0 .7 8 - 1 .5 1
2 .1 7 - 2 .5 7
1 .1 5 - 1 .3 1
9 1 .3
Serum levels of osteocalcin, alkaline phosphatase, PTH, phosphate, total calcium and ionized calcium are shown as well. Patient No. 2 had histochemical aluminum deposition on the mineralization front.
Results
In table 2, diagnosis of bone histomorphometry, mea surements of BBC and serum levels of osteocalcin, alka line phosphatase, PTH, phosphate, total calcium and ion ized calcium are given with ranking of the patients according to BBC values. Median value of BBC was found to be 91.3 ml/min/60 kg BW (range 71.2-147.5). As mentioned earlier, the plasma clearance of 99mTc-MBP consisted of the sum of the bone, peritoneal and renal 99mTc-MBP clearances. We found that the peritoneal clearance of 99mTc-MBP (Clpcr.MBp) constituted in median 5.1% (range 3.5-8.8) of the plasma clearance of 99mTcMBP whereas the median renal 99mTc-MBP clearance (Clkki.MBp) accounted for 2.3% (range 1.2-5.2). The sums of Clpcr.MBP and Clkid.MBP were not statistically signifi cantly different from the total plasma clearance of 5lCrEDTA. Five patients had BBC values within the normal range, even though 4 of these patients had abnormal bone histo morphometry (table 2). The highest values of BBC were found in 2 patients with osteitis fibrosa, while 2 other
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patients with the same histomorphometric diagnosis had values of BBC within the normal range (table 2). Altogeth er, no relations between BBC values and the diagnosis of bone biopsies were found. The highest values of osteocal cin, alkaline phosphatase, and PTH were found in pa tients suffering from osteitis fibrosa. In table 3, indices of bone resorption and formation are given as well as addi tional histomorphometrical profiles of investigated pa tients. Table 4 shows coefficients of correlation for some of the most relevant bone indices and the relation to the noninvasive markers of bone metabolism evaluated. No significant correlations were found between BBC values and any of the bone histomorphometric variables mea sured. A positive correlation was seen between serum lev els of osteocalcin and resorption and active resorption surface (p < 0.05), as well as tetracycline labelled surface, bone formation rate, surfaces, volume and tissue referents (p < 0.01). Furthermore, levels of alkaline phosphatase showed significant correlations to mineral appositional rate, tetracycline labelled surface, and bone formation rate, volume referent (p < 0.05). PTH were found to cor relate significantly to resorption surface (p < 0.02) and to active resorption surface, mineral appositional rate and corrected apposition rate (p < 0.05).
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Statistical Evaluations Data are presented as mean ± standard deviation and median and range when appropriate. Statistical evaluation was performed by linear regression analysis. Differences were considered significant when p < 0.05.
Table 3. Histomorphometrical profile of investigated patients (No. 1-8)
Pt. No.
RS, %
ARS. %
OS.%
OV,%
MAR pm/day
LS mm
M(f) pm/day
BFRS BFRV pm 3/pm 2/yr %/yr
1 2 3 4 5 6 7 8
5.2 1.4 0.9 3.0 2.3 1.4 4.6 3.2
0.92 0.37 0.16 0.95 0.38 0.35 0.90 0.71
29.2 43.4 15.1 30.5 13.5 6.8 10.8 24.3
6.0 9.2 2.1 5.8 1.5 0.8 1.8 5.1
1.1 0.0 0.0 0.9 0.9 1.0 0.8 1.0
13.0 0.0 0.0 3.5 3.5 0.9 5.3 26.3
0.5 0.0 0.0 0.1 0.3 0.4 0.4 0.6
39.6 0.0 0.0 6.4 11.2 6.9 13.7 41.5
67.4 0.0 0.0 13.5 17.4 12.6 27.5 91.8
18.9 0.0 0.0 2.6 3.9 2.2 4.0 16.2
Mean ± SD
2.8 1.6
0.59 0.31
21.7 12.3
4.0 2.9
0.7 0.5
6.6 9.0
0.3 0.2
14.9 16.5
28.8 33.3
6.0 7.3
BFR, %/yr
RS = Resorption surface: ARS = active resorption surface: OS = osteoid surface: OV = osteoid volume; MAR = mineral appositional rate; LS = tetracycline-labelled surface; M(f) = corrected apposition rate; BFRS v , = bone forma tion rate, surfaces, volume and tissue referents, respectively.
The 24-hour whole body retention of bisphosphonate (WBR) was introduced in 1978 and has since then been used as a noninvasive measure of bone metabolism [7], However, WBR has one major drawback, namely its dependency of renal function. This was avoided when Hyldstrup et al. [7] described a method allowing an esti mation of osseous tracer uptake independent of the renal function (the BBC), which allows investigation of bone metabolism in patients undergoing dialysis. This noncompartmental model is based on the use of 51Cr-EDTA as a cotracer and requires that renal and other nonosseous clearances of 99mTc-MBP and 5lCr-EDTA are similar [7], In the present study the model has been further adapted to CAPD so that the clearance of 99mTc-MBP from plasma constitutes not only the sum of bone and renal clearances but the peritoneal clearances of 99mTc-MBP as well. This is based on the assumption that both substances are cleared from plasma by glomerular filtration, and diffusion/filtration takes place into the extravascular space, including peritoneal fluid, while only MBP is taken up by bone in regions of increased bone turnover [7], Limited data are available on BBC as a radionuclide method for assessment of renal osteodystrophy. Gruenewald et al. [15] compared the 51Cr-EDTA/99mTc-MBP ratio in 44 patients undergoing hemodialysis and in 13 on CAPD against serum calcium, phosphate, alkaline phos phatase, PTH, bone scan images, forearm bone density as well as radiology. Thirty-nine hemodialysis patients and 8
Table 4. Coefficient o f correlation between histomorphometric variables. BBC and serum levels of osteocalcin, alkaline phosphatase and PTH
Variables
BBC
Osteocalcin
Alkaline PTH phosphatase
Resorption RS ARS
0.14 0.17
0.69* 0.71*
0.56 0.68
Osteoid OS OV Bone dynamics MAR LS M(0 BFRS BFRV BFR,
-0.46 -0.38 0.42 0.59 0.64 0.39 0.51 0.24
0.29 0.32 0.57 0.86*** 0.58 0.87*** 0.87*** 0.88***
-0.15 -0.11 0.73* 0.74* 0.62 0.66 0.71* 0.60
0.78** 0.69* -0.22 -0.14 0.69* 0.43 0.70* 0.65 0.59 0.67
See table 3 for abbreviations. * p < 0.05: ** p < 0.02; *** p < 0.01.
patients undergoing CAPD had a second study performed approximately 1 year later. In the initial study, 93% had abnormal isotope ratios of 51Cr-EDTA/99mTc-MBP with a poor correlation between this ratio and bone density. In a later study, they found agreements about the direction of changes between serum alkaline phosphatase and 5lCrEDTA/99mTc-MBP ratio in 81 %, but in 39% of these 81 %
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Discussion
the serum levels of alkaline phosphatase remained within the normal range. Based on this study the authors con cluded that the 5lCr-EDTA/99mTc-MBP ratio is a simple test of quantifying bone uptake of MBP for assessment and follow-up of renal osteodystrophy. Neither bone biopsies nor the serum levels of osteocalcin were per formed. BBC values were converted into ml/min/60 kg body weight before analysis of correlations to serum levels of alkaline phosphatase, osteocalcin and PTH were per formed (table 4). This was done as variations in bone mass are likely to influence bone clearance of MBP. The main observation in this study is the lack of correlation between BBC and bone histomorphometry as well as between BBC and the diagnosis of bone biopsies. How ever, serum levels of osteocalcin gave more information of the bone variables than the more time consuming BBC test and are of some use for evaluation of bone resorption and dynamics in patients undergoing CAPD as a noninvasive parameter. Serum levels of alkaline phosphatase and PTH gave less information of bone metabolism in the investigated dialysis patients, although some significant correlations were found. No single explanation of these results appears. However, it is reasonable to believe that differences in the sensitivity of the various markers could be of significance. Moreover, there is every probability
that the investigated formation markers represent various aspects of the osteoblast function [ 14], Four of our 8 patients, having had a bone biopsy show ing osteitis fibrosa, had elevated serum alkaline phospha tase. The elevations in the levels of alkaline phosphatase were reflected in individual values of osteocalcin and PTH. This is contrary to our previous findings that CAPD per se removes nearly no alkaline phosphatase but substantial amounts of PTH [5]. In conclusion, the present study has emphasized that the BBC technique can be used independently of renal function in patients treated with CAPD but gives no information on bone histomorphometry or diagnoses of bone disease in these patients. Serum osteocalcin corre lated best with resorption and bone dynamics indices. Levels of alkaline phosphatase and PTH were, however, of more limited value. Acknowledgements We wish to thank technician-in-chief Ingelise Siegumfeldt and technician Janne Berg for their enthusiastic and careful assistance during the tracer part of the study. Osteocalcin measurements were performed due to grants from the Danish Rheumatism Association. P.J. was supported in part by grants from the Foundation of Else & Mogens Weddell-Wedellsborg and the Danish Rheumatism Associa tion.
1 Nolph KD: Overview of peritoneal dialysis 1991 (handout). I Ith Annu Conf Periton Dial 1991. p 1. 2 Heaf JG. Joffe P. Podenphant J. Andersen JR: Non-invasive diagnosis of uremic osteodystro phy: Uses and limitations. Am J Nephrol 1987; 7:203-211. 3 Heaf JG, Podenphant J. Joffe P, Andersen JR. Fugleberg S, Braendstrup O: The effect of oral aluminium salts on the bone of non-dialysed uremic patients. Scand J Urol Nephrol 1987: 21:229-233. 4 Joffe P, Heaf JG: Vitamin D and vitamin Dbinding protein kinetics in patients treated with continuous ambulatory peritoneal dialy sis. Periton Dial Int 1989:9:281-284. 5 Joffe P, Heaf JG: The effect of continuous ambulatory peritoneal dialysis on biochemical products related to renal osteodystrophy. Trace Elem Med 1989:6(4):169-172. 6 Joffe P. Podenphant J, Heaf JG: Bone histol ogy in CAPD patients: A comparison with hemodialysis and conservatively treated chronic urémies; in Khanna R, et al (eds): Advances in Peritoneal Dialysis 1989. Toron to, Périt Dial Bull, 1989. pp 171-176.
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7 Hyldstrup L. McNair P. Ring P. Henriksen O: Studies on diphosphonate kinetics. II. Whole body uptake rate during constant infusion - a refined index of bone metabolism. Eur J Nucl Med 1987;12:581-584. 8 Mosekilde L, Hasling C. Charles P. Tigehoj Jensen F: Bisphosphonate whole body reten tion test: Relations to bone mineralization rate, renal function and bone mineral content in osteoporosis and metabolic bone disorders. Eur J Clin Invest 1987; 17:530-537. 9 Brown JP. Delnas P, Malaval C, Edouard MG. Meunicr PJ: Serum bone GLA-protein: A spe cific marker of bone formation in post-meno pausal osteoporosis. Lancet 1984;i: 1091 — 1093. 10 Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology: Recommended methods for deter mination of four enzymes in blood. Scand J Clin Lab Invest 1974;33:281-306.
11 Hyldstrup L, Clemmensen I, Jensen BA, Transbol I: Non-invasive evaluation of bone forma tion: Measurements of serum alkaline phos phatase, whole body retention of diphospho nate and serum osteocalcin in metabolic bone disorders and thyroid disease. Scand J Clin Lab Invest 1988:48:611-619. 12 Joffe P. Olsen F. Heaf JG, Gammelgaard B. Podenphant J: Aluminium concentration in se rum. dialysate. urine and bone among patients undergoing CAPD. Clin Nephrol 1989:5:133— 138. 13 Podenphant J, Heaf JG, Joffe P: Metabolic bone disease and aluminium contamination in 38 uremic patients. Acta Pathol Microbiol Im munol Scand 1986;94:1-6. 14 Podenphant J, Johansen JS. Thomsen K, Riis BJ. Leth A, Christiansen C: Bone turnover in spinal osteoporosis. J Bone Miner Res 1987:6: 497-503. 15 Gruenewald SM, Fawdry RM. Farlow DC, Steward JH: CrEDTA/TcMDP ratio - a new radionuclide method for assessment of renal osteodystrophy (abstract). Kidney Int 1988:33: 139-140.
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References
