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Relationships
BetweenCalciumandPhosphorus
Homeostasis,
Parathyroid
HormoneLevels,BoneAluminum,andBone
Histomorphometry
in PatientsonMaintenance
Hemodialysis
P. NILSSON,
F. MELSEN,3 J. MALMAEUS,*
B.G. DANIELSON,
and L. MOSEKILDE4
and reprints:
Per Nilsson, Department of Internal Medicine, University Hospital, S-751 85, Uppsala, Sweden.
Abstract
Introduction
Hypocalcemia,
secondary to phosphate retention and deficiency of 1,25-dihydroxycholecalciferol,
is important in the
pathcgenesis of the defective bone mineralization regularly
observed in nondiafyzed uremic patients (Malluche et al.,
21
22
rate (M/t)~mlday.
The mean distance between tetracycline lines In all double-labeled areas divided by the interval in days
(t) between the two labelings, uncorrected (u) for obliquity of the plane
of section.
Laboratory Methods
Monthly determinations of serum calcium, phosphate, and alkalrne
phosphatase were performed by standard laboratory methods. Serum
calcium was adjusted for serum albumin concentration by 0.019
mmolll for each g/l that the individual albumin concentration deviated
from the normal mean of 46 g/l. Serum aluminum was determined at
least once in 10 patients, using atomic absorption photometry. As
estimated in healthy individuals, normal values are below 10 pgll.
lmmunoreactive serum parathyroid hormone (PTE& was measured
every 2 to 3 months by a radioimmunoassay using
l-labeled bovine
PTH (lnolex) and sheep antiserum (S478) against bovine and porcine
PTH. This assay measures intact PTH and the C-terminal two thirds of
the molecule (Hehrmann et al., 1980). The reference range, as estimated from 50 apparently healthy individuals, IS 0.40 to 1.20 arbitrary
units II (arbU/I). For each patient all biochemical data collected during
the B-month period before and at the time of the bone biopsy were
pooled. and the average values of the individual variables were used in
the statistical analysis.
Histomorphometric
V, = SlrtilabI x M/t
This represents theamount of new bone mineralized per unit of time per
unit of trabecular bone surface.
Bone formation rate, BMU level, surface referent (5V,rBMuJ~m3/~m2
per day as:
analysis.
This defines the average time lag between osteoid formation and
subsequent mineralization (Melsen and Mosekilde, 1978b).
Statistical methods
Statistical analysis of differences between group means was performed with the Wilcoxon rank sum test for independent samples.
Possible relationships between biochemical and histomorphometric variables were analyzed by calculation of the Spearman rank
correlation coefficient (Colton. 1974).
fractional trabecular bone volume (tVracttb))~m3/~m3, The fraction of a given volume of total trabecular bone tissue occupied by
mineralrzed and unmineralized trabecular bone
Results
Fractional formation surfaces (Sr,,t~rJ~m/~m.
teoid surface expressed
surface
Serum biochemistry
Serum calcium (normal 2.20-2.60 mmol/l) for the 6-month
period preceding the bone biopsy was 2.44 -+ 0.02 mmolll
(mean f SEM), and all patients were consistently normocalcemic. Hyperphosphatemia
was noted in 13/17 (mean
1.78 f 0.12 mmol/l, normal 0.76-l .44 mmol/l). Mean serum
alkaline phosphatases were slightly elevated at 6 + 2 rkat/l
(normal 0.8-4.8 &t/l). All patients had elevated PTH (5.5 +
1 .O arbU/I, normal 0.40-l .20 arbU/I). Serum aluminum was
elevated in 9/l 0 studied patients to a mean value of 46 f 14
fig/l (normal < 10 pg/l).
Fractional resorption
BMU, base multrcellularunit, the functional group of cells (osteoclasts arm osteoblasts) tha! are responsible for the turnover of a structural bone unit (I e., a packet in
trabecular bone)
Bone histomorphometry
The results of the histomorphometric
Table I for the whole group of patients and controls. The fractional trabecular bone volume was not different in patients and
controls, but the mean values of both fractional resorption surfaces and fractional formation surfaces were increased in the
patient group (P c 0.001). The mean width of osteoid seams
was slightly increased (P < 0.05). The analysis of the dynamic
variables related to tetracycline labeling yielded normal mean
values for fractional labeled surfaces. Thus the fractional labeled formation surfaces were reduced (P < 0.05) since the
fractional formation surfaces were increased. Appositional rate
and bone formation rates at both levels were normal, whereas
the mineralization lag time was prolonged (P c 0.05).
There was a close correlation between the indices of bone
resorption and formation (turnover), expressed as fractional
resorption surfaces and bone formation rate at tissue level,
respectively (r = 0.81, P c 0.0001). Although the mean bone
turnover rate (bone formation rate, tissue level) was similar in
patients and controls, the variance was much greater in the
patient group (F = 17.4, P c 0.001). It was therefore found
convenientto divide the material into two groups on the basis of
a bone turnover rateabove(groupA,n
= 9)or below(group B,
n = 8) the mean value in the control group. The two groups
were comparable regarding sex and age, but the patients in the
low turnover group (B) had spent a longer time on HD (group A
11 k 2 months, group B 29 f 8 months, mean f SEM,
P c 0.05). Histomorphometrically, there were no differences in
trabecular bone volume or in any of the static parameters of
bone formation (Table II). Fractional resorption surfaces were
higher in the high turnover group (A) (P < 0.01). The results of
Table I. Bone hisotmorphometry
23
the tetracycline double-labeling were clearly different; the law
turnover group exhibited lower fractional labeled surfaces and
highly depressed fractional labeled formation surfaces (P <
0.001). The mean appositional rate was the same in both
groups, but in the low turnover group the boneformation rate at
BMU level was reduced (P c 0.01) and the mineralization lag
time was prolonged (P < 0.01). Serum calcium, phosphate,
and alkaline phosphatase were similar in both groups. The
mean serum PTH was lower in the low turnover group (group A
7.8 + 1.5 arbU/I, group B 2.8 + 0.2 arbU/I, mean + SEM, P
c 0.01). The two parathyroidectomized
patients were found in
this group. They were not excluded from the analysis, since they
had maintained normocalcemia for a long time without the use
of vitamin D or calcium supplements, indicating residual functioning parathyroid tissue.
Fractional aluminum-stained
trabecular
surfaces were
higher in patients with low bone turnover (P < 0.05) (Table II).
This was not reflected in any differences in serum aluminum
concentration, in the duration of treatment with, or in the calculated total ingested dose of aluminum hydroxide. There was no
correlation between fractional aluminum-stained surfaces and
time on HD. In the whole patient material, fractional aluminumstained surfaces did not correlate with fractional formation
surfaces but were inversely related to fractional resorption
P < 0.05). The relationships
surfaces (r = -0.51,
between aluminum staining and the results of tetracycline labeling are illustrated in Figure 1. Inverse relationships were
found between fractional aluminum-stained surfaces and fractional labeled formation surfaces (r = - 0.52, P < 0.05) and
bone formation rates at tissue (r = - 0.55, P < 0.05) and BMU
levels (r = -0.70, P < O.Ol), whereas fractional aluminumstained surfaces were directly related to mineralization lag time
VI@,,
pm3/pm3
Sf=l(f)
pm/pm2
Controls
0.28 ? 0.02
0.21 * 0.01
(0.15 - 0.50)
(0.12 - 0.32)
0.49 f 0.05
0.20 f 0.01
(0.19 - 1.0)
(0.06 - 0.30)
Sf=W
~m/pm*
0.11 f 0.02
0.05 f 0.01
(0 - 0.24)
(0.03 - 0.07)
uW,
13.0 f
flm
1.7
(4.6 - 34.9)
9.6 + 0.53
0.20 f 0.04
0.15 f 0.02
(0.001 - 0.60)
(0.09 - 0.27)
Sf,Zt(lkJlrJ
fim2/pm2
(0.001 - 1 .OO)
0.71 f 0.07
0.64 k 0.05
0.60 f 0.02
(0.001 - 1.08)
(0.61 - 0.71)
0.13 f 0.04
0.09 + 0.01
(0.001 - 0.57)
(0.06 - 0.17)
sVf(EW,
pm3/~m per day
0.33 * 0.10
0.44 + 0.05
(0.001 - 1.04)
(0.25 - 0.68)
23 f 3
44
h,
days
(9 -
m)
Values are mean f SEM ( median). Ranges are indicated in parentheses. ns = not significant.
P < 0.001
P < 0.001
P < 0.05
ns
P < 0.05
(0.30 - 1 .OO)
am/day
M/t
ns
(6.5 - 12.1)
Sfrwab)
pmlfim
0.40 f 0.07
Patients vs controls
(11 - 37)
ns
ns
ns
P < 0.05
24
in patients with high turnover (group A) and low turnover (group B).
Group B
Group A
(n = 9)
(n = 8)
A vs 0
0.28 + 0.03
(0.16 - 0.50)
.I 0.26 + 0.03
ns
Sr=WI
j.4m2/pmz
0.49 f 0.07
(0.19 - 0.78)
0.50 * 0.09
(0.27 - 1 .O)
S*a(r)
~m2/pm2
0.15 f 0.02
(0.06 - 0.24)
0.07 -c 0.02
(0.001 - 0.15)
Wit
rmlday
0.65 f 0.06
(0.40 - 0.96)
0.62 f 0.10
(0.10 - 1.08)
S(r=t(lab)
pml~m
0.30 f 0.05
(0.12 - 0.60)
0.07 +- 0.02
(0.0001 - 0.15)
P < 0.01
SrWMWnl
pm21~m2
0.64 -t 0.07
(0.40 - 1 .O)
0.15 -c 0.04
(0.0001 - 0.38)
P < 0.001
Vkt,b,
am3/pm3
(0.15 - 0.40)
14 f 3.2
(8.1 - 35)
12 f 1.7
(4.6 - 21)
WI
pm
ns
P < 0.01
ns
ns
0.21 + 0.05
(0.10 - 0.57)
0.04 f 0.01
(0.001 - 0.08)
P < 0.01
0.43 f 0.08
(0.23 - 1.04)
0.10 -c 0.03
(0.001 - 0.28)
P < 0.01
33.6 + 5.7
(9.0 - 57.4)
115*
(36.4 - m)
P < 0.01
days
S*acf(All
pm*/~m
0.05 f 0.02
(0 - 0.16)
0.21 -c 0.06
(0 - 0.48)
P < 0.05
%
V
t,
rate.
and biochemical
interrelations were noted between any of the determined biochemical variables nor between serum biochemistry and patient age, time on HD, or time between the diagnosis of renal
disease and the start of HD.
Discussion
The histomorphometric findings in this study of a normal bone
turnover rate (bone formation rate, tissue level) and increased
fractional formation and resorption surfaces are in accordance
with what has been reported by others for dialysis patients
without symptoms of musculoskeletal disease (Nielsen et al.,
1980a). However, even though the mean bone turnover rate
was normal, the patients showed a much greater variation of
this variable than the controls. The material was therefore subdivided into two groups with highly different and nonoverlapping bone turnover rates. The two groups had almost identical
mean values of the static parameters of bone formation. The
fractional resorption surfaces were lower in patients with low
bone turnover, but even in this group the mean value was
slightly above that found in the controls. Such a combination of
increased formation and increased resorption surfaces would
result either from an increased frequency of activation of trabecular bone remodeling foci (BMU) or from an increased
lifespan of the resorptive and formative processes (Frost,
1969).
fract(lab/f)
0.6
25
. .
1
svf
0 6 vm3/pm2/d
prnVprn2
l.O-
0.6-
,
0 0.1
0.3
Sfract(Al)
0.5
,=:
ph/vrn2/d
O.Sl
.
l
.
.-
,_
4
S-PTH
fract(Al)
12
20
arbU/I
S4PTH
svf(BfvlU)
vm5/pm2/d
svf(BMU)
pm3/pm2/d
1.2
1000
.
200 I
12
20
arbU/I
tm
days
1.2
.
0.8
0.8
200
1-4
0.4 i ;,
1..- l. * .
0t**
0.1
O
I Y3 25
l
SfractiAl)
100
I.
l*
0. .* .*
o??
0 0.1
100
.
I
0.3
Sfract(Al)
0.5
Fig. 1. Fractional labeled formation surfaces (S,rtiC,a&, bone formation rates at tissue (V,) and BMU (sV,(BMu,)
levels, and mrneralrzatron lag
time (t,,,) in relation to fractional aluminum-stained surfaces (Sfrac,& in
17 HD patients.
20
S!PTH
::bU/I
4.
:
..
S-PTH
12
20
arbU/I
26
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Lea parametrea biochimiquea refl&ant Ihom6oataale calcique et phoaphor6a Sinai quo la fonction parathyrdidlenne ant 6t6 6tudi6s, parall6tetnant b
lhlatomo@om6trle oaaeuae aprea double maquage par is t6tracycllne et coloration de ialumlnium, chez 17 maladea Mmodialydr depulaa molna
6 mola et na pr6aentant pas de aymptomea oaaeux. Une corrdlatlon 6troite a 6t6 trouv6e entra lea taux a6rlquea de la Parathormona (PTH) duna Part,
lea surfaces de &sorption et leavlteaaea doat6oformation dmma part, 6 la fola mt nlveau tlaaulalre et au nlveau de iunit6 baaale multlcebutalre (UgM)
de remodelege. Lea maladea ont pu 6tre dlvla6a en un groups 6 haut nlvaw de remodelaga ayant una mln6rallaatlon normale, et un grOUpe L bae r&ear
de remodelege ayant un Important d6faut de mln6rallaatlon. La deuxleme groupe 6tait en outre carect6rld par un taux plus baa de PTH et una plus
grand0 extenalon dea surfaces trab6culalrea relatives coior6ea pour Ialuminium. Pour Ienaemble dea maiadea, lea surfaces reiatlvea color&a pour
iaiuminlum 6talent invemement propottlonnellas aux surfaces marqu6ea par la t6tracycll~ et h la v&easedoat6oformatlon6valu6e au nlveaude IUBM
et au nlveau tlaaulalre, mala aana relation avec Ianclennet6 dea dlalyaeaou la doaecumui6e dhydroxyde daluminlum lngti.
Cea donn6eamontrent
quo la PTH ou lea facteura 116s6 la PTH, outre leur effet actlveteur aur le remodelage oaaeux, atlmulent directement la formatlon oaaeuaa cheziea
diaiya68, et qua Iincorporation daiumlnium dana 10seat aaaoci6e 6 un d6tart progreaaff de la min6rallaation oaSeua&