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Effect of oral 125-dihydroxyvitamin D and calcium on glucocorticoid-induced osteopenia in patients with rheumatic diseases.

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EFFECT OF ORAL 1,25-DIHYDROXYVITAMIN D AND
CALCIUM ON GLUCOCORTICOID-INDUCED
OSTEOPENIA IN PATIENTS WITH
RHEUMATIC DISEASES
THOMAS R. DYKMAN, KATHLEEN M. HARALSON, OSCAR S. GLUCK, WILLIAM A. MURPHY,
STEVEN L. TEITELBAUM, THEODORE J. HAHN, and BEVRA H. HAHN
Twenty-three rheumatic disease patients with
glucocorticoid-induced osteopenia (defined by measurement of forearm bone mass) completed an 18-month
double-blind, randomized study to assess the effect of
oral calcium and 1,25-dihydroxyvitamin D (1,25-OH2D)
or calcium and placebo on bone and mineral metabolism. Intestinal 47Ca absorption was increased (P <
0.05) and serum parathyroid hormone levels were suppressed (P < 0.01) by 1,25-OH2D (mean dose 0.4 pgl
day); however, no significant gain in forearm bone mass
occurred, and bone fractures were frequent in both
groups. In the 1,25-OH2D group, histomorphometric
analysis of iliac crest biopsy specimens demonstrated a
decrease in osteoclasts/mm2 of trabecular bone (P < 0.05)
and parameters of osteoblastic activity (P < 0.05),
indicating that 1,25-OH2D reduced both bone resorption and formation. We conclude that 1,25-OH2D
should not be used for treatment of glucocorticoidinduced osteopenia. Since patients receiving calcium
and placebo did not exhibit a loss of forearm bone
mass, elemental calcium supplementation of 500 mg
daily might be useful to maintain skeletal mass in
patients receiving long-term glucocorticord therapy.
-~
From the Departments of Medicine and Radiology, Washington University School of Medicine and the Department of
Pathology, The Jewish Hospital of St. Louis, St. Louis, Missouri,
and the Department of Medicine, UCLA School of Medicine, Los
Angeles, California.
Thomas R. Dykman, MD; Kathleen M. Haralson, RPT;
Oscar S. Gluck, MD; William A. Murphy, MD; Steven L. Teitelbaum, MD; Theodore J. Hahn, MD; Bevra H. Hahn, MD.
Address reprint requests to Bevra H. Hahn, MD, Department of Medicine, U C I A School of Medicine, Center for Health
Science, Room 47-139, 10833 Le Conte, Los Angeles, CA 90024.
Submitted for publication March 27, 1984; accepted in
revised form July I I , 1984.
Arthritis and Rheumatism, Vol. 27, No.12 (December 1984)
Oral administration of glucocorticords in humans results in severe osteopenia caused by several
mechanisms (1-3). Histologic studies of bone in humans receiving glucocorticoids demonstrate decreased
bone formation (4-6) and increased numbers of osteoclasts and osteoclast-resorbing surfaces (5-7). The
decrease in formation rate probably represents a direct
effect of glucocorticoids on osteoblasts. Specifically,
glucocorticoids decrease the recruitment of progenitor
cells to osteoblasts and the synthesis of collagen and
noncollagen protein by preexisting osteoblasts (8,9).
The mechanism by which glucocorticoids increase bone resorption is more controversial. In vitro,
glucocorticoids inhibit osteoclast activity (3, lo). However, in vivo, glucocorticoids greatly decrease intestinal calcium absorption (2,11,12) and may stimulate
parathyroid hormone (PTH), thus providing an indirect stimulus to osteoclastic activity (6,13). This model
is consistent with the observation that parathyroidectomy abolishes the osteoclastic response of bone to
glucocorticoids (14), and suggests that there is resorption of bone in glucocorticoid-induced osteopenia,
because PTH stimulation overrides the inhibition of
osteoclasts by glucocorticoids.
Previous studies have demonstrated that oral
therapy with calcium and vitamin D or 25-hydroxyvitamin D (25-OHD) improves metabolic and histologic
parameters in patients with glucocorticoid-induced
osteopenia (6). Such therapy increases intestinal calcium absorption, decreases serum PTH, decreases
bone resorption as demonstrated by iliac crest biopsies, and increases appendicular bone mass. To examine whether a more potent stimulator of intestinal
calcium absorption, such as 1,25-dihydroxyvitamin D
(1,25-OH2D), would produce a more favorable re-
1337
sponse, w e assessed the use of 1,25-OH2D and calcium in rheumatic disease patients with glucocorticoid-induced osteopenia.
PATIENTS AND METHODS
Thirty ambulatory patients with rheumatic diseases
and glucocorticoid-induced osteopenia were chosen for
study. Criteria for inclusion included: 1) treatment with
glucocorticoids (>5 mg prednisone equivalents/day for >6
months); 2) the presence of glucocorticoid-induced osteopenia as defined by a greater loss of metaphyseal than
diaphyseal bone mass of the radius (l5,16): 3) no history of
nephrolithiasis and a creatinine clearance >60 cdminute; 4)
no evidence of liver disease or gastrointestinal malabsorption. Specifically excluded from study were patients who,
within the previous 6 months, had taken medications known
or suspected to alter bone mineral metabolism (anticonvulsants, cytotoxic agents, estrogens, androgens, fluoride, or
vitamin D in doses >400 IU/day).
Of the 30 patients enrolled, 7 did not complete the
study; 3 were withdrawn due to noncompliance, 2 died from
rheumatic disease, I discontinued glucocorticoid therapy,
and 1 was lost to followup. The distribution of clinical
diagnoses in the 23 remaining patients who completed the
study was 12 patients with rheumatoid arthritis, 8 with
systemic lupus erythematosus, I with scleroderma, I with
seronegative arthritis, and 1 with undifferentiated connective
tissue disease.
All studies were performed at the Clinical Research
Center of Washington University School of Medicine. On
admission, all patients were interviewed by a dietician to
determine intake of vitamin D and calcium. Functional
status was also evaluated by the criteria of Steinbrocker et a1
(17). Bone mass of the distal radius was determined by a
previously described single photon absorption technique
(15), and was determined at 2 locations: a metaphyseal site, 2
cm proximal to the distal end of the radius, and a diaphyseal
site, one-third the total length of the radius from its distal
end. Values were calculated and recorded as gm/cm2. The
coefficient of variation for this method is 3% at the diaphyseal site and 3-5% at the metaphyseal site. Intestinal 47Ca
absorption was determined by the forearm counting technique of Wills et al (18) before initiation of treatment and at
the end of the study, while the patients were still receiving
treatment. A 100-mg oral dose of 47Cawas given at 8:00 A M
after an overnight fast. Blood samples were then drawn and
serum calcium, inorganic phosphatase, alkaline phosphatase, and creatinine concentrations and 24-hour urinary
calcium and creatinine levels were determined by an automated analyzer (Technicon Instruments, Tarrytown, NY).
These assays were repeated monthly.
Serum FTH, 25-OHD, and 1,25-OH?D concentration
analyses were performed by Dr. Graeme Bryce at Roche
Research Center, Nutley, NJ. Serum PTH was determined
by the radioimmunoassay technique of Slatopolsky et al(19),
serum 25-OHD by ?he competitive protein-binding assay of
Haddad and Chyu (20), and serum 1,25-OHzD by the method
of Mallon et al(21). These assays were performed at 3-month
intervals throughout the study.
All patients had radiographic analyses at the time of
entry and at the study’s end; flat plates of the abdomen were
reviewed for kidney stones, and radiographs of the thoracolumbar spine, femoral heads, and hands were reviewed for
fractures. Transiliac bone needle biopsies were performed
before initiation of treatment and at the end of the study.
After biopsy, each specimen was fixed in neutral buffered
formalin, embedded in methyl methacrylate, and cut into
nondecalcified sections on a Jung model K sledge microtome
(American Optical Corp., Buffalo, MY). An entire section
taken from each biopsy, including both cortices and the
intervening trabeculae, was stained by 3 modification of the
Goldner technique (22) and histologically quantitated using
an Osteoplan Image Analyzer (Carl Zeiss, Inc., New York,
NY).
In the pretreatment and post-treatment biopsy samples, histomorphometric parameters were determined in
cortical and trabecular bone. These determinations were
made “blindly” by one of us (SLT) who was not involved in
patient care. Parameters measured were: a) percent trabecular bone volume, or the percent of trabecular space occupied
by bone matrix; b) percent cortical bone volume, or the
percent of cortical bone space occupied by bone matrix; c)
percent relative osteoid volume, or the percent of trabecular
bone matrix which is nonmineralized; d) percent total osteoid surface, or the percent of trabecular surface covered by
nonmineralized bone matrix; e) percent osteoblastic osteoid
surface, or the percent of trabecular bone surface covered by
osteoid lined by characteristic cuboidal osteoblasts; r) number of osteoclasts per square millimeter of trabecular space.
The study design was a double-blind protocol in
which patients were randomly assigned to receive either
1,25-OH?D (begun at 0.25 &day) or a placebo capsule of
identical color and size. All patients received 500 mg of
elemental calcium (calcium carbonate) per day and a multivitamin containing 400 IU of vitamin D. Data were analyzed
by Student’s t-test and Mann-Whitney rank sum test as
noted.
RESULTS
Pretherapy demographic and biochemical parameters. Pretherapy clinical characteristics and dietary history for the placebo- and 1,25-OH2D-treated
patients w ho completed the full 18-month trial are
shown in Table 1 . There were no significant differences in age, sex, or race. Most patients were white
women. Functional class and mean daily d o se of
glucocorticoid were similar in both groups. Although
duration of prcvious glucocorticoid therapy was somewhat longer in the placebo group, this difference was
not significant. Differences in dietary intake of calcium
and vitamin D were not significant.
Pretherapy serum concentrations of total calcium, phosphate, and alkaline phosphatase were not
significantly different in the placebo group compared
with the 1,25-OH2D group for those w h o completcd
the study (Table 2). Although higher initial serum 25-
1338
DYKMAN ET AL
Table 1. Pretherapy clinical characteristics and dietary history*
1,25-OHZD
group
(n = 13)
P
1.60 2 0.22
46.5 f 3.8
3/10
419
1.61 2 0.14
NS
NS
NS
NS
11.3 t 4.2
12.2
2.6
NS
7.3 2 1.6
189 2 28
877 2 83
4.8 f 1.6
145 ? 25
725 f 74
0.25
0.25
0.20
Placebo group
(n = 10)
Age
Males/females
Blackdwhites
Functional class (ranking units)
Glucocorticoid dose (mg prednisone
equivalents/day)
Duration of glucocorticoid
therapy (years)
Vitamin D (IU/day)
Calcium (mg/day)
51.5
4.7
5
1/9
218
f
* Values represent the mean 2 SEM. Probability calculated by Student’s f-test. NS = not significant.
OHD and I ,25-OH2Dconcentrations were found in the
1,25-OH2D group, mean values for both parameters
were within the normal range in both groups. Serum
PTH concentrations were not elevated and fell within
the range of normal in both groups. Urine studies
disclosed no significant differences in calcium excretion or creatinine clearance. In both groups, mean
intestinal calcium absorption (% of a 100-mg oral dose)
was decreased compared with normal values established in previous studies conducted in our laboratory
(6).
Pretherapy bone mass was measured in the
forearm by the single photon absorption technique
(Table 3). Values are expressed as gm/cm’ and as
percentage of normal values that were reported previously for age- and sex-matched normal individuals
from the midwest (15). Bone mass in all patients was
significantly decreased, showing mean percent reduction of 28.3 2 2.2 in the metaphyseal region of the
Table 2.
radius ( P < 0.05) and 14.0 _t 2.6 in the diaphyseal
region (P < 0.05). The absolute changes observed and
the disproportionately greater loss of bone mass in the
metaphyseal region than in the diaphyseal region correlate to previously reported observations in 2 laboratories (15,16), on the pattern of bone loss in glucocorticoid-induced osteopenia. Pretreatment bone mass was
not significantly different between placebo and 1,25OHzD groups.
Response to 1,25-OH2D and calcium administration. All patients received supplements of 500 mg of
elemental calcium in 3 divided doses each day,
throughout the study period. Patients receiving 1,25OH’D were started at a dosage of 0.25 pglday, and if
urinary calcium levels remained <350 mg/24 hours,
the dosage was increased by 0.25 pg every 1 or 2
months up to a maximum of 1.0 Fg/day. During the
study, hypercalciuria (>350 mg/24 hours) occurred in
8 of the 13 1,25-OH2D-treated patients, and the dosage
Pretherapy biochemical and intestinal 47Ca absorption data*
Placebo group
Normal ranee
Serum values
Total calcium (mg/dl)
Phosphate (mg/dl)
Alkaline phosphatase (mIU/ml)
25-OHD (ng/rnl)
1 ,25-OH2D (pg/ml)
PTH (PI eq/ml)
24-hour urinary calcium excretion
(mg/gm creatinine)
Creatinine clearance
(mUminute/l.73 m’)
47Ca absorption (% of
100 mg load)
* Values represent the mean
2
FTH = parathyroid hormone.
(n
= 10)
1,25-OHZD
group
(n = 13)
P
9-10.3
2.5-4.5
35-1 I5
12-40
15-70
0-15
9.17 5 0.16
3.91 2 0.17
91.3 5 10.9
14.3 5 1.5
31.8 t 3.0
5.35 2 0.67
9.28 rt 0.09
3.79 f 0.15
71.0 5 6.8
19.9 rt 2.3
45.6 2 4.9
4.86 ? 0.63
NS
NS
0.15
0.07
0.03
NS
50-300
153 5 17
128 rt 12
0.25
75-125
94.2
5
6.3
94.2
2
8.5
NS
51-76
41.4
5
5.6
48.9
-t
5.9
NS
SEM. Probability calculated by Student’s r-test. NS = not significant;
THERAPY OF GLUCOCORTICOID-INDUCED OSTEOPENIA
1339
Table 3. Pretherapy measureiiient of forearm bone mass*
~~
Normal
values
(n = 23)
All patients
(n = 23)
0.541 2 0.017
-
0.388 2 0.014t
11.7 2 2.3
0.744
0.641
86.0
Site
Metaphyseal
gm/cm2
% of normal
Diaphyseal
gm/cm2
% of normal
0.015
2
-
2
2
0.023t
2.7
Placebo
group
(n
0.369
70.4
10)
1,2.5-OHZD
group
(n = 13)
* 0.022
* 3.5
0.403 2 0.018
74.0 f 3.1
=
0.600 % 0.040
83.0 2 4.9
0.673
88.3
f
2
0.026
2.9
* Bone mass was determined in the radius by the single photon absorption technique (see Patients and
Methods). Values represent the mean 5 SEM. Normal values determined from age- and sex-matched
healthy normal individuals from the midwest.
t Significantly different from normal values, P < 0.05, by Student’s 1-test.
was reduced. By the end of the study, the mean dose
of 1,25-OH2D was 0.4 pglday. In contrast, only 3 of
the 10 patients receiving placebo developed hypercalciuria. In these patients, calcium supplementation
apparently resulted in transient elevation of calcium
levels in the urine. Hypercalcemia (serum calcium
> 10.4 mg/dl) occurred only in patients receiving 1,25OH2D;4 of these 13 patients developed hypercalcemia
during the study, and the dosage was reduced. Overall, 12 of these 13 patients developed either hypercalcemia or hypercalciuria, which prevented our increasing the dosage of 1,25-OH2Dto 1.0 pglday.
Compared with the pretherapy values shown in
Table 2, at the end of the 18-month study, 24-hour
urinary calcium levels were higher in both groups
(Table 4), but the increases reached significance only
in those patients receiving 1,25-OH2D( P < 0.05). No
patient showed evidence of nephrolithiasis on radiographic examination of the abdominal area. Mean
creatinine clearance values at the end of the study
were not significantly different from pretherapy values
in either group (data not shown). Mean serum calcium
Biochemical and intestinal 47Caabsorption in 1,25-OH2D
and placebo groups at study end*
Table 4.
Placebo group
(n = 10)
24-hour urinary calcium
(mp/gm creatinine)
Serum calcium (mddl)
3’% increase in 47Caabsorption
Serum iPTH (PI eq/ml)
194 2 17
*
I ,25-OH2D group
(n = 13)
245
2
14t
2
0.16
9.39 0.08
2.2 f 8.0
9.56
31.2
4.50 C 0.43
3.07 2 0.24t
* 13.1.t
* Values represent the mean 2 SEM. FTH = parathyroid hormone.
f Significantly different from pretherapy values, P < 0.05 by paired
t-test.
$ Significantly different from placebo-treated patients, P < 0.05 by
Mann-Whitney rank sum test.
levels at the end of the study did not significantly
increase in either group. There was a 31% increase
above pretherapy values ( P < 0.05) in intestinal 47Ca
absorption for 1 ,25-OH2D-treated patients, compared
with a 2% increase for placebo-treated patients. Concurrent with the increase in intestinal 47Caabsorption,
serum PTH concentration fell significantly in 1,25OH$-treated patients ( P < O.Ol>, but not in those
receiving placebo.
At 18 months, serum levels of 1,25-OH2D in the
group receiving 1,25-OH2D (32.3
3.3 pg/ml) were
similar to those of the placebo group (35.8 5 6.3 pg/
ml). Failure to detect an elevation in serum 1,25-OH*D
in patients receiving 1 ,25-OH2D may have been due to
the method of collection. Sera were drawn 12 hours
after the last dose, and because of the short half-life of
1,25-OH2D (2-5 hours), it is unlikely that elevated
levels would be demonstrated. Verification of compliance was assessed by pill counts throughout the study.
Changes in bone mass of the radius during the
study were measured by the single photon absorption
technique (15) and are shown in Figure 1 as percent
change from baseline values. By the end of the study,
bone mass at the diaphyseal and metaphyseal sites
demonstrated a small (-5%), but not statistically
significant, increase in the 2 groups. Bone fractures,
however, were frequent in both groups during the 18month study; 3 of 13 1,25-OH2D-treated patients had
non-traumatic vertebral and/or extravertebral fractures compared with 4 of 10 placebo-treated patients.
Results of a previous study (6), showing changes in
bone mass of the radius, are also shown in Figure 1.
This previous study compared therapy with 25-OHD
(40 &day) plus 500 mg elemental calcium with therapy of placebo plus 100 mg of elemental calcium over a
12-month period. Criteria for selection of patients
were similar t‘o the current study; however, this previ-
*
DYKMAN ET AL
1340
1.25-Oi+D*500MGCakium
500 NG Calcium
A 25-0nD 500 NG Cakium
A 100% Calcium
the baseline demonstrates that 25-OHD therapy increases appendicular bone mass in glucocorticoidinduced osteopenia. It is of interest that a small, but
not statistically significant, decrease in both diaphysea! and metaphyseal bone mass was observed in patients who received 100 mg of elemental calcium per
day.
Histomorphometric analysis of bone biopsy
samples taken before treatment and after completion
of the study were available in 21 of 23 patients (2
patients refused a repeat biopsy at the study end)
(Table 5). Prior to therapy, the bone histology of the
placebo- and 1,25-OH2D-treated patients was similar.
Therapy with 1,25-OH2D had no effect on the histomorphometrically determined cortical and trabecular
bone volumes. It did, however, lead to significant
decrements of osteoclasts/mm2 of trabeculum ( P <
0.005) and osteoblastic osteoid surface ( P < 0.01). A
>40% reduction in relative osteoid volume and total
osteoid surface also occurred in the I ,25-OH2D group,
but these changes were not significant (P > 0.10 for
both). The placebo-treated patients also had decreases
in the number of osteoclasts/mm’ of trabeculum and
parameters of osteoblastic activity, but these changes
were not significant (P > 0.25 for both).
Bone density and histologic data were analyzed
by Mann-Whitney rank sum analysis (data not shown),
in addition to the Student’s t-test analysis shown in
Table 5 and Figure 1. There was no significant gain in
metaphyseal or diaphyseal bone mass in the placebo or
1,25-OH2Dgroups. As shown in Table 5 , 1,25-OH2D
therapy significantly decreased osteoclasts/mm’
of trabeculum and osteoblastic osteoid surface (P
< 0.05), but decreases in relative osteoid volume and
total osteoid surface were also significant by rank sum
0
u1
v)
DIAPHYSEAL MASS
METAPHYSEAL MASS
*.
0 +15
*.
I*
R2
-101
I
I
3
I
1
I
I
12
15
MONTHS OF THERAPY
6
9
18
Figure 1. Percent change in diaphyseal and metaphyseal bone
mass, measured by photon absorption technique, in 13 patients
receiving 1,25-OH2D + 500 mg elemental calcium and 10 patients
receiving placebo + 500 mg elemental calcium. Vertical bars represent 1 SEM. Also shown are values obtained in a previous study (6)
of 9 patients receiving 25-OHD + 500 mg elemental calcium and 8
patients receiving placebo + 100 mg elemental calcium. *Values are
significantly different from baseline measurements ( P < 0.05). by
paired t-test.
ous study revealed that therapy with 25-OHD resulted
in significant gains in diaphyseal (P < 0.05) and
metaphyseal (P < 0.01) bone mass when compared
with baseline values. Improvement in bone mass from
Table 5.
Bone histomorphometric parameters before and at the end of treatment*
Placebo group (n
=
9)
1,25-OH2Dgroup (n
=
12)
Parameter
Pretreatmen1
Post-treatment
Pretreatment
% cortical bone volume
% trabecular bone
90.4 t 1.4
16.1 2 1.0
90.1 -c 2.2
16.6 -t 1.7
91.6 -t 1.3
16.6 t 1.6
92.8 2 0.8
16.8 t 1.4
0.20
2
0.07
0.1 I 2 0.05
0.24 2 0.04
0.08
f
0.03t
2.21
5
0.68
1.27 2 0.44
1.34 f 0.35
0.36
f
0.14t
2.38 2 0.72
1.91
2.10 2 0.56
0.92 f 0.47
15.2 2 3.8
13.2 2 3.8
volume
No. osteoclasts/mm’ of
trabeculum
% osteoblastic osteoid
surface
% relative osteoid
volume
% total osteoid surface
5
0.63
11.7 -t 2.4
Post-treatment
6.8
r+_
3.0
* Values represent the mean k SEM. Two subjects refused post-treatment biopsies and are therefore
not included.
t Significantly different from pretreatment values, P < 0.01 by paired r-test.
THERAPY OF GLUCOCORTICOID-INDUCED OSTEOPENIA
analysis ( P < 0.05). No significant changes in histologic parameters were found by rank sum analysis in the
placebo group . Hence, rank sum analysis of bone
density and histologic parameters further supports our
opinion that 1,25-OH2D therapy decreases osteoblastic activity and thereby prevents significant gains in
bone mass. Finally, the response to therapy in the 6
blacks in this study was assessed. Responses of blacks
in placebo or 1,25-OH2Dgroups were comparable with
the responses of whites.
DISCUSSION
This study demonstrates that oral therapy with
1,25-OH2Dand calcium does not significantly increase
appendicular bone mass in rheumatic disease patients
with glucocorticoid-induced osteopenia. Over the 18month study, bone fractures occurred in approximately one-fourth of the patients receiving treatment with
1,25-OH2D. Toxicity was also frequent; at least 1
episode of hypercalciuria or hypercalcemia occurred
in 12 of the 13 patients receiving 1,25-OH2Dtherapy.
Our attempt to increase the dose of l,25-OH2D to 1.0
pg per day partially accounted for the common occurrence of toxicity. 1,25-OH2D is approximately 100
times more potent than 25-OHD in stimulating intestinal calcium absorption and 1,000 times more potent
than vitamin D2 (2). Despite the common occurrence
of toxicity, however, we found no evidence that
patients with normal renal function sustained any longlasting complications. No patient developed nephrolithiasis, and there was no significant deterioration in
creatinine clearance in the group receiving 1,25OH2D.
The common occurrence of bone fractures
among patients in this study (7 of 23 patients) is not
unexpected given the low appendicular bone mass
measured by the photon absorption technique at study
entry. This technique has been used recently to survey
asthmatics receiving long-term glucocorticoid therapy
(16). As in rheumatic disease patients receiving longterm glucocorticoid therapy (2,15), a greater loss of
bone-mineral mass was found at the metaphyseal site
of the forearm than at the diaphyseal site. Fractures
were found in -40% of the asthmatics who had longterm glucocorticoid therapy .
Measurement of appendicular bone mass does
not necessarily reflect the mineral mass of bone at
vertebral or other appendicular sites. Seeman et a1 (23)
demonstrated that in idiopathic or iatrogenic Cushing’s syndrome, loss of mineral mass of bone at
vertebral sites is greater than that at appendicular
1341
sites. Nevertheless, since our patients had vertebral as
well as extravertebral fractures, it is likely they had
low vertebral bone mineral mass. The small number of
patients in our study may have prevented us from
detecting a difference in fracture rates between the
placebo and 1 ,25-OH2Dgroups. Examination of metabolic and histologic parameters, however, provides
insight into the failure of 1,25-OH2D to significantly
increase appendicular bone mass.
Therapy with 1,25-OH2D increased intestinal
47Ca absorption, suppressed serum PTH, and decreased osteoclast number as demonstrated by iliac
crest biopsies. These effects are similar to those reported after 12 months of 25-OHD therapy, which
revealed that appendicular bone mass increased by
15% in patients with glucocorticoid-induced osteopenia (6) (see Figure I). However, in the present
study, in addition to suppressing osteoclastosis, significant decreases in osteoblastic osteoid, relative osteoid volume, and total osteoid surface were found in
patients receiving 1 ,25-OH2D. This parallel fall in
parameters of osteoid and osteoclast number indicates
a reduction in the number of bone remodeling units, an
observation consistent with suppression of both skeletal resorption and formation. Hence, the inhibitory
effects of 1,25-OH2D on osteoblastic activity may
cancel out beneficial effects promoted by increases in
calcium absorption and suppression of osteoclastosis.
In vitro experiments demonstrate that I ,25OH2D suppresses osteoblast function. 1 ,25-OH2D inhibits alkaline phosphatase, citrate decarboxylase activity, and collagen synthesis in isolated fetal rat
osteoblast-like cells (24). This latter effect of treatment
is potentiated by the addition of glucocorticoids (25).
The decrease in osteoblastic parameters in the 1,25OH2D group may not have prevented a small increase
in bone mass. Both the placebo and the 1,25-OH2D
group demonstrated an -5% increase in metaphyseal
mass, although this increase did not reach statistical
significance. Since this small increase was seen in both
groups, it may be secondary to the beneficial effect of
calcium supplementation.
Conversion of 25-OHD to 1,25-OH2D by the
kidney is tightly regulated in humans. Large doses of
25-OHD result in physiologic levels of I ,25-OH2D and
conversion of 25-OHD to 24,25-OH2D (26). Conversion of 25-OHD to 24,25-OH2D, rather than to 1,25OHZD, may allow for a different effect of 25-OHD on
bone and mineral metabolism. We cannot exclude the
possibility that 24,25-OH2D may have some role in the
response we have attributed to 25-OHD. It is also
possible that lower doses of 1,25-OH2D than those
-
1342
used in this study may have improved intestinal 47Ca
absorption and suppressed bone resorption, but avoided suppression of osteoblastic activity.
It is of interest that pretherapy serum PTH
levels in our patients and in those of I other report
were normal (12). While this does not correspond to
other series where glucocorticoid-treated patients
were found to be hyperparathyroid (6,13), it is possible
that skeletal sensitivity to the hormone may be more
important than absolute levels of PTH. For example,
short-term exposure of isolated bone cells to glucocorticoids increases their response to PTH (27-29). However, recent evidence suggests that this enhanced
sensitivity of bone to PTH is lost after long-term
treatment with glucocorticoids (30).
At present, the mechanism by which PTH may
contribute to bone resorption in glucocorticoid-induced osteopenia remains uncertain. Although serum
PTH is decreased during 25-OHD or 1,25-OH2Dtherapy, we cannot exclude that other mediators, such as
calcitonin or unmeasured metabolites of vitamin D,
may also be responsible for suppression of osteoclastosis.
Although 1,25-OH2D therapy did not significantly increase skeletal mass in this study, patients
who received placebo plus elemental calcium supplementation of 500 mg/day and a multivitamin containing
400 IU of vitamin D had no detectable loss of metaphyseal or diaphyseal bone mass after 18 months of
therapy. This is in contrast to an earlier study in which
patients who received 100 mg daily of elemental calcium had an apparent small decrease of diaphyseal and
metaphyseal mass (6). It is possible that calcium
supplementation may stabilize bone mass in '/patients
receiving long-term glucocorticoid therapy. Recently,
such supplementation (- 1,000 mg elemental calcium/
day) has been demonstrated to result in improvement
of calcium balance and bone mass in idiopathic osteoporosis (3 1,32). Furthermore, the incidence of vertebral compression fractures is diminished by approximately 50% in postmenopausal women who have
received calcium supplementation (33).
Based upon these observations, it is our opinion
that all patients treated long-term with glucocorticoids
should receive elemental calcium supplementation
(500-1,000 mg/day) and the minimum daily requirement of vitamin D (400 IU/day). Although the risk of
this regimen is probably low, urinary calcium levels
should be monitored every 6 months to be assured that
they remain <350 mg/24 hours. For patients with
levels of <I20 mg/24 hours, we recommend adding 25-
DYKMAN ET AL
OHD (40 pg/day) and adjusting the dosage, if needed,
to keep urinary calcium <350 mg/24 hours. Vitamin D
(50,000 units 3 timedweek) may also be used, but if
toxicity occurs with vitamin D therapy, it persists
much longer than with 25-OHD. None of these therapies has been shown to prevent fractures in glucocorticoid-induced osteopenia, and they should be considered experimental. At present, we believe that 1,25OH2D should not be used for the management of
glucocorticoid-induced osteopenia.
ACKNOWLEDGMENTS
We are grateful to Peggy Hart and Lorraine Whiteley
for their expert secretarial assist2nce. The Osteoplan Image
Analyzer was a gift from the Jewish Hospital Auxiliary.
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