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Evaluation of factors associated with glucocorticoid-induced osteopenia in patients with rheumatic diseases.

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Official Journalof the American Rheumatism Association Section of the Arthritis Foundation
significant loss of bone mass (1-3). The degree of loss
is more severe in areas of the skeleton with a high
content of trabecular bone, such as vertebrae and ribs.
It is less striking in the diaphyses of long bones, which
consist primarily of compact cortical bone (4-6).
We have previously used single photon absorptiometry to measure appendicular bone mineral mass
in normal individuals and rheumatic disease patients
(7-10). Measurements at diaphyseal and metaphyseal
sites of the radius demonstrate a constant relationship
between bone mineral mass at the diaphyseal site and
that at the metaphyseal site, both in normal individuals
and in most patients with conditions associated with
osteopenia (for example, idiopathic osteoporosis).
However, in osteopenia associated with glucocorticoid therapy, there is a greater loss of metaphyseal
mass (MM) than diaphyseal mass (DM), and the
DM:MM ratio increases (7-10). A combination of
factors may account for this observation. First, the
metaphyseal site contains a higher proportion of trabecular bone (>25%) than the diaphyseal site (-5%)
(1 1). Second, the metaphyseal site has a greater surface area than the diaphyseal site, and endosteal
resorption of cortical bone may be more easily measured at the metaphyseal site.
Since measurement of DM:MM ratios provides
a simple, inexpensive, and rapid method of identifying
patients with glucocorticoid-induced osteopenia, we
have measured these ratios in 161 patients with various rheumatic diseases treated with long-term glucocorticoid therapy. This report evaluates whether different glucocorticoid treatment regimens and patient
characteristics are associated with glucocorticoid-induced osteopenia and bone fractures.
In 161 ambulatory rheumatic disease patients
receiving long-term prednisone therapy, diaphyseal
mass (DM) and metaphyseal mass (MM) of the forearm
were measured by single photon absorptiometry, and
bone radiographs were reviewed when available. Multivariate analysis of treatment and patient characteristics
demonstrated that glucocorticoid-induced osteopenia
(defined as an elevated DM:MM ratio) and bone fractures occurred with similar frequency in patients of each
sex, in whites and blacks, in patients with various
rheumatic diseases, and in patients receiving different
regimens of prednisone therapy. However, large cumulative doses of prednisone were associated with elevated
DM:MM ratios as well as with bone fractures, and
menopause or age 2250 years (males or females) was
associated with bone fractures. We conclude that longterm therapy with various prednisone regimens results
in glucocorticoid-induced osteopenia and fractures. This
affect is cumulative, occurs in all patient groups, and
results in more bone fractures in certain groups.
It has long been recognized that long-term
administration of oral glucocorticoids can result in a
From the Department of Medicine and the Mallinckrodt
Institute of Radiology, Washington University School of Medicine,
St. Louis, Missouri, and the Department of Medicine, UCLA
School of Medicine and Wadsworth VA Hospital, Los Angeles,
Supported in part by NIH training grant AM-07279-06.
Thomas R. Dykrnan, MD; Oscar S. GLuck, MD; William A .
Murphy, MD; Theodore J. Hahn, MD: Bevra H. Hahn, MD.
Address reprint requests to Bevra H. Hahn, MD, Department of Medicine, UCLA School of Medicine, Center for Health
Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90024.
Submitted for publication June 26, 1984; accepted in revised form October 26. 1984.
Arthritis and Rheumatism, Vol. 28, No. 4 (April 1985)
36 1
Patient selection. All ambulatory patients attending
rheumatology clinics at Washington University between July
1979 and December 1980 were screened by review of written
medical records. Any ambulatory patients who met the
following criteria were invited to participate in the study: 1)
at least 6 weeks of daily or alternate-day prednisone therapy:
2) no prior therapy with sodium fluoride, supplemental
calcium, or vitamin D in doses exceeding the minimal daily
requirement of 400 IU/day; 3) no evidence of significant
renal dysfunction (creatinine >1.5 mg/dl); 4) no clinical or
chemical evidence of intestinal malabsorption, liver disease,
or primary hyperparathyroidism.
Of 366 patients who met these criteria, 205 refused to
participate and were not further evaluated. In the 161 who
consented, the following information was obtained:
1. Historical information. Sex, age, race, diagnosis, and prednisone dosage were recorded in every
patient. Cumulative dose of prednisone for each patient was also calculated from review of the written
medical record and/or personal interview. by adding
daily doses over the entire length of therapy. Functional class was assigned based upon the patient’s
activities at the time of study (12). Dieticians estimated
calcium intake by review of food consumption during
the 8 weeks before testing.
2. Radiographic studies. Single photon absorptiometry of the radius, as described by Cameron et a1
(13), was performed in all 161 patients. This method
utilizes a monochromatic beam from a Iz5I source. The
forearm is wrapped in a tissue-equivalent material to
maintain constant thickness and is transversely
scanned. The arm was carefully positioned so that the
photon beam passed in a perpendicular path to the
long axis of the radius. Two sites of the radius of the
nondominant arm were scanned: a metaphyseal site 3
cm proximal to the distal end of the radius, and a
diaphyseal site at a distance one-third the total length
of the radius from its distal end.
Results of 3 scans at each site were averaged, and the
bone mineral mass (gm/cm2) was calculated. In our laboratory, the coefficient of variation was *3% at the diaphyseal
site and *3-5% at the metaphyseal site (7). The DM:MM
ratio was then calculated for each patient. This method has 2
advantages. First, it is known that although the DM and MM
may decrease with age, the loss of bone mineral occut-s in
parallel so that the DM:MM ratio remains constant regardless of age, sex, or race (7,8). Second, because glucocorticoid therapy is associated with a disproportionate loss of
MM, elevation of the DM:MM ratio would identify patients
with glucocorticoid-induced osteopenia (7,8).
In the 161 patients, all available radiographs taken 2
years before or at the time of study were also reviewed, and
the presence of bone fractures was recorded. Radiographs of
both vertebral and extravertebral sites were available on 93
Statistical methods. Analysis of data was performed
with assistance from the Division of Biostatistics at Washington University. Chi-square testing of contingency tables
with Yates’ correction and Student’s t-tests were performed
as noted. A multiple linear regression model was used for
analysis of treatment and patient characteristics and
DM:MM ratios. Adequacy of this model is represented by F
= 4.28, P = 0.0001. Multiple logistic regression was utilized
for analysis of treatment and patient characteristics and
fractures. The adequacy of this model is represented by the
goodness of fit x2 = 80.0, P = 0.24.
Patient characteristics. Characteristics of the
161 rheumatic disease patients studied are shown in
Table 1. Fifty percent were 250 years old. The majority of patients were females (82%), 56% of whom were
postmenopausal. Sixty-one percent of the patients
were white and all remaining patients were black. The
2 most frequent disease categories were rheumatoid
arthritis (53%) and systemic lupus erythematosus
(33%). The remaining 22 patients (14%) included 4
patients with scleroderma or its variants, 4 with polpmyositis/dermatomyositis, 4 with undefined or mixed
connective tissue disease, 4 with Reiter’s syndrome, 2
with juvenile rheumatoid arthritis, and 1 patient each
with polyarteritis nodosa, BehGet’s syndrome, ankylosing spondylitis, and psoriatic arthritis. Functional
classification by Steinbrocker’s criteria (1 2) revealed
that 41% of these patients were in functional class 1,
55% were in class 11, and 4% were in class 111. (The
low percentage in class I11 is not surprising since only
patients who were ambulatory were included in the
study.) Drug therapies were recorded in 120 patients
who had medical records that were complete enough
to enable an assessment of drugs taken in the previous
2 years. Many patients took nonsteroidal antiinflammatory agents (51%) or aspirin (24%). Cytotoxic
agents or estrogens were used infrequently.
Glucocorticoid therapy. The mean dosage of
prednisone taken by the 161 patients at the time of
absorptiometry was 15.6 t 1.1 mg/day (mean k SEM),
with a range of 1-80 mg/day. Thirty-two patients (20%)
were receiving alternate-day rather than daily therapy.
Duration of therapy ranged from 42-9,275 days, with a
SEM of 1,473
116 days, approximately 4
years. Cumulative dose of prednisone was 16.0 f 1.3
gm (mean k SEM), with a range of 0.2-1 18.5 gm.
Absorptiometry. In a healthy St. Louis population including all ages above 18 years, the DM:MM
ratio remains constant and has a value of 1.37 t 0.12
SD) (7). In this study, any DM:MM values
that were more than 2 standard deviations above this
normal mean (i.e., 21.62) were defined as elevated.
Sixty-one of 161 patients receiving prednisone (38%)
Table 1. Characteristics of patients with normal or elevated diaphyseal mass:metaphyseal mass
(DM:MM) ratios
DM:MM ratio
All patients
Characteristic *
Menopausal status (females)
Rheumatic disease
Functional class$
Cytotoxic drugs
1331161 (82)
281161 (18)
79/100 (79)
211100 (21)
54/61 (88)
7/61 (12)
81/161 (50)
801161 (50)
501100 (50)
501100 (50)
30161 (49)
31/61 (51)
691123 (56)
54/123 (44)
37171 (52)
34/71 (48)
32/52 (61)
20152 (39)
981161 (61)
63/161 (39)
59/100 (59)
411100 (41)
39/61 (63)
22161 (37)
86/161 (53)
531161 (33)
22/161 (14)
551100 ( 5 5 )
341100 (34)
I11100 (11)
31/61 (51)
19/61 (31)
11/61 (18)
631153 (41)
84/153 ( 5 5 )
hi153 (4)
41192 (45)
48/92 (52)
3/92 ( 3 )
22/61 (36)
36/61 (59)
3/61 ( 5 )
61/120 (51)
291120 (24)
9/120 ( 8 )
5/120 (4)
37/67 ( 5 5 )
16/67 (24)
3/67 (4)
2/67 (3)
24153 (45)
13/53 (25)
6/53 (9)
3/53 (6)
* RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; NSAID = nonsteroidal
antiinflammatory drugs.
t Probability by chi-square analysis, between patients with normal and those with elevated DM:MM
ratios. N S = not significant.
$ Information not available on every patient.
had elevated ratios characteristic of glucocorticoidinduced osteopenia.
Demographic characteristics including sex, age,
menopausal status, race, disease category, functional
class, and nonglucocorticoid therapies were not significantly different in patients with normal DM:MM
ratios versus those with elevated ratios (Table I).
Weekly calcium ingestion was also not significantly
different in the 2 groups: patients with elevated
DM:MM ratios ingested 5.26 -+ 0.56 gmiweek (mean 2
SEM) of calcium, versus 4.51
0.50 gm/week in
patients with normal ratios. Since demographic characteristics were not significantly different in patients
with normal and elevated DM:MM ratios, these characteristics probably did not account for the greater
loss of bone mineral mass in patients with elevated
DM:MM ratios.
Bone fractures. Radiographs of both vertebral
and extravertebral sites were available for review in 93
of the 161 patients who had absorptiometry. To evaluate whether review of radiographs in only some patients would potentially increase the observed number
of fractures, demographic parameters were compared
in the 93 patients who had radiographs versus the 68
patients who did not. There was no significant difference in sex, age, race, disease category, mean daily
dose of prednisone, or cumulative dose (data not
shown). However, functional class was significantly
better in patients with radiographs ( I .57 t 0.05, mean
? SEM) than in those without ( I .76
0.08). ( t = 2.01,
P < 0.05). This may have led to a finding of fewer
fractures in patients who had radiographs.
Twenty-eight of the 93 patients with radiographs (30%) had bone fractures (Table 2). Fractures
were found significantly more often in patients with
elevated DM:MM ratios (42%) than in patients with
normal ratios (19%). When fractures were analyzed by
site of occurrence, 17 patients (18%) had vertebral
Table 2. Bone fractures and diaphyseal mass:metaphyseal mass
(DM:MM) ratio in 93 rheumatic disease patients with radiographs
and absorptiometry
No. (%) of
All patients
Elevated DM:MM ratio
Normal DM:MM ratio
28/93 (30)
19/45 (42)*
9/48 (19)*
* P < 0.05, chi-square analysis.
fractures and 17 had extravertebral fractures (data not
shown). Sites of extravertebral fractures included feet
and hands (6 patients), humerus (4 patients), ribs (4
patients), tibia (2 patients), and femoral neck (1 patient). Elevated DM:MM ratios were found in l l of the
17 patients with vertebral fractures (65%) and in 12 of
the 17 patients with extravertebral fractures (71%).
Association of previous glucocorticoid therapy
with elevated DM:MM ratios and fractures. Patients
receiving different doses of prednisone at the time of
absorptiometry had similar frequencies of elevated
DM:MM ratios and fractures (Table 3). However,
since doses taken by patients at the time of absorptiometry may not reflect dosages taken previously, the 32
patients receiving 5 5 mg prednisone/day were carefully evaluated. Review of medical records disclosed that
10 of these patients had consistently taken 5 5 mg
prednisone/day in the past. Three of these 10 (30%)
had elevated DM:MM ratios (data not shown). Patients receiving alternate-day therapy at any dose were
also evaluated. They did not have better DM:MM
ratios; 11 of 32 (34%) had elevated ratios (data not
High cumulative doses of prednisone were associated with a significant increase in the frequency of
elevated DM:MM ratios. This trend was found, by
multivariate analysis, to be independent of patient age;
elevated DM:MM ratios were not more common in
patients 250 years of age than in those 4 0 years.
High cumulative doses were also associated with
elevated DM:MM ratios in various subgroups versus
the patient group as a whole (data not shown), including females (P = 0.0003), males (P = 0.05), patients
with rheumatoid arthritis (P = 0.01), and patients with
systemic lupus erythematosus ( P = 0.0005). Fractures
were also found significantly more often in patients
with high cumulative doses of prednisone.
Elevated DM:MM ratios and bone fractures.
When patients were analyzed by sex, age, menopausal
status, race, disease category, and functional class, no
significant differences in the frequency of elevated
DM:MM ratios were found (Table 4). However, age
2 5 0 years and menopause were each associated with a
significant increase in fractures. Increases in fractures
in patients age 250 were similar in men and women
(data not shown); 5 of 11 men 250 years old (45%) and
14 of 38 women 250 years old (37%) had fractures.
Among patients age 150, 13 of the 19 with
fractures (68%) had elevated DM:MM ratios. Among
postmenopausal females, 10 of the 15 with fractures
(67%) had elevated ratios. Therefore, evidence for
glucocorticoid-induced osteopenia was found in twothirds or more of the patients age 250 who had
fractures and in two-thirds or more of the postmenopausal females with fractures. No significant differences in number of fractures were detected in female
patients versus male, whites versus blacks, or patients
with different rheumatic diseases.
Using photon absorption techniques and bone
radiographs, we examined glucocorticoid-induced osteopenia in ambulatory rheumatic disease patients
Table 3. Association of previous prednisone therapy with elevated diaphyseal mass:metaphyseal
mass (DM:MM) ratios and with fractures
Patients with elevated
DM:MM ratio (%)
Daily dose
5 5 mg
6-20 mg
>20 mg
Cumulative dose
<10 gm
10-30 gm
>30 gm
11/32 (34)
42/105 (40)
8/24 (33)
18/77 (23)
25/61 (40)
18/23 (78)
* By multiple regression analysis. NS
= not significant.
Patients with
fracture (%)
6/19 (32)
18/58 (31)
4/16 (25)
10/45 (22)
10/33 (33)
8/15 (53)
Table 4. Elevated diaphyseal mass:metaphyseal mass (DM:MM) ratios and fractures, by patient
Patients with elevated
DM:MM ratio (%)
4 0
2 50
Menopausal status
Rheumatic disease
Functional class
Patients with
fracture (%)
7128 (25)
541133 (41)
5/14 (36)
23/79 (29)
31/80 (39)
30181 (37)
9/44 (20)
19/49 (39)
20153 (37)
31/69 (45)
7136 (19)
15/40 (38)
39/98 (40)
22/63 (35)
21/63 (33)
7130 (23)
31186 (36)
19/53 (37)
11122 (50)
15/44 (34)
9134 (26)
4/15 (26)
22/63 (35)
36/84 (42)
316 (50)
8/44 (1 8)
18/47 (38)
212 (100)
* RA = rheumatoid arthritis; SLE = systemic lupus erythematosus.
I’ By multiple regression analysis. NS = not significant.
receiving long-term prednisone therapy. Since patients
with a history of osteopenia or fracture may have
preferentially enrolled in this study, some selection
bias may have occurred. Furthermore, since radiographs of only two-thirds of the patients were reviewed, further bias may have occurred, so the observed incidence of fractures may be artificially high.
The rates of vertebral and extravertebral fractures we
found (18% each) were slightly higher than those
reported in other unselected populations (7-17%).
However, our goal in performing this study was to
evaluate whether certain glucocorticoid regimens or
patient characteristics are associated with glucocorticoid-induced osteopenia and bone fractures. Therefore, although some selection bias was possible, comparisons of treatment and patient characteristics
within the study population should remain valid.
Among patients with rheumatoid arthritis, vertebral fractures have been reported in 8-17% of those
receiving glucocorticoid therapy (2,3,14). The only
other large series of rheumatic disease patients studied
is a recent preliminary report of 309 patients attending
an outpatient clinic in Salt Lake City; approximately
80% of the patients in this series had rheumatoid
arthritis. Vertebral fractures were found in 15% of
patients receiving glucocorticoids, compared with 7%
of patients not receiving glucocorticoids (15). Al-
though these series are not directly comparable due to
differences in patient diagnoses, functional class, and
duration of therapy, the occurrence of vertebral fractures in 18% of our patients is not inconsistent with
these reports. It is of interest that extravertebral
fractures and vertebral fractures were found with the
same frequency in our patients. In our experience,
extravertebral fractures may be a significant source of
Our decision to use DM:MM ratios was based
largely on our previous experience showing a characteristic elevation of DM:MM ratios in patients receiving long-term glucocorticoid therapy (7-10). Although
a single preliminary report did not find this relationship (16), a recent publication has used this methodology and identified elevated DM:MM ratios in asthma
patients receiving long-term glucocorticoid therapy
(17). Other investigators have measured vertebral as
well as forearm bone mineral mass using photon
absorptiometry in individuals with Cushing’s syndrome. In 17 patients with iatrogenic and idiopathic
Cushing’s syndrome, a much greater loss of bone
mineral mass was found at vertebral sites than at
proximal or distal forearm sites (6).
Although measurements at either proximal or
distal forearm sites may not be as sensitive in detecting
loss of vertebral bone mineral as measurements at
vertebral sites, our study provides evidence that measurement at 2 appendicular sites and calculation of the
DM:MM ratio may identify many patients who have
loss of bone mass at vertebral sites. Elevated DM:MM
ratios were found in approximately two-thirds of the
patients with vertebral fractures in our study. Elevated
DM:MM ratios were also found in a similar number of
patients with extravertebral fractures.
The inability of DM:MM ratios to identify all
patients with bone fractures in this study may reflect
the many factors which contribute to bone fractures in
patients receiving glucocorticoid therapy. In addition
to loss of bone mass induced by glucocorticoid therapy, inactivity due to poor functional class, age, and
menopause may contribute to low bone mass and
fracture (3,14). In this study, patients with elevated
DM:MM ratios had significantly more fractures (42%)
than patients with normal DM:MM ratios (19%). Although our study supports an association between
elevated DM:MM ratios and bone fractures, we do not
believe a single measurement of DM:MM ratio can be
used to predict risk for fracture in an individual
Multivariate analysis of DM:MM ratios and
previous glucocorticoid therapy in this study demonstrated that the cumulative dose of prednisone is the
most important factor which determines glucocorticoid-induced osteopenia. Patients who had taken a
cumulative dose of >30 gm of prednisone had the
highest incidence of fractures (53%) and elevated
DM:MM ratios (78%). Several previous reports have
also emphasized the association between cumulative
glucorticoid dose and radiographic osteopenia or bone
fracture (15,18). Two studies of rheumatic disease
patients, however, did not emphasize this relationship
(3,141. Cumulative dosage in both of these latter
studies was < l o gm, and duration of therapy may not
have been long enough to produce a significant increase in radiographic osteopenia or fractures. Correlations between elevated DM:MM ratios and large
cumulative dose of glucocorticoids were present in
various patient subgroups in our study, including those
with rheumatoid arthritis, those with systemic lupus
erythematosus, males, and females.
Although previous investigators have suggested
that therapy with low daily doses of glucocorticoids is
not associated with glucocorticoid-induced osteopenia
(3,19), our earlier (10) and present results demonstrate
that some patients receiving daily low-dose therapy, as
well as patients on alternate-day regimens, may have
elevated DM:MM ratios. Bone mineral loss during
glucocorticoid therapy is due to decreased bone formation and increased bone resorption (9,20,21). Glucocorticoids inhibit intestinal calcium absorption and
inhibit osteoblast differentiation and osteoblast synthesis of collagen and noncollagen protein. Although
oral doses of prednisone > 10 mg are usually required
to inhibit intestinal calcium absorption (22), we have
found some patients receiving I10 mg/day who have
decreased intestinal calcium absorption (unpublished
observations). Furthermore, the dose of prednisone
that inhibits bone formation has not been determined,
and low daily or alternate-day doses could possibly
inhibit bone formation in some individuals. Overall.
we believe our data suggest that long-term therapy at
any dose may produce glucocorticoid-induced osteopenia.
Analysis of patient characteristics demonstrated that the frequency of elevated DM:MM ratios was
similar in different patient groups. Comparisons by
sex, race, functional class, and various disease categories disclosed no significant differences. These findings suggest that the risk for development of glucocorticoid-induced osteopenia (elevation of DM:MM ratio)
is similar in all patient groups. However, fractures
were significantly increased in patients age 250 years
(males or females) and in postmenopausal females.
One explanation for the higher number of fractures in
these elderly patients would be that preexisting low
bone mass secondary to age or postmenopausal status
results in an increased risk of fracture. However,
elevated DM:MM ratios were found in two-thirds or
more of the patients who were 2 5 0 years old or were
postmenopausal females with fractures. Therefore,
evidence for glucocorticoid-induced osteopenia was
common in these patients, and glucocorticoid-induced
Table 5. Patient and treatment characteristics associated with
elevated diaphyseal massmetaphyseal mass ratios and/or bone
Definite association
Cumulative prednisone
Age 2 5 0 years (male
and female)
N o association
Sex (excluding
Disease category
Current prednisone
bone loss superimposed on low bone mass may have
increased bone fractures.
One previous study has demonstrated that radiographic evidence of osteopenia of the vertebral
spine is more common in women 250 years old
receiving glucocorticoids (3). A recent study has also
demonstrated that glucocorticoid therapy increases
the risk of hip fractures in postmenopausal women
(23). Although males have a greater bone mass than
females at all ages, other series have also noted that
men as well as women develop fractures during glucocorticoid therapy (15,17,24).
No previous studies have evaluated fracture
rates in blacks versus whites receiving glucocorticoid
therapy. Although blacks have a greater bone mass
throughout life than whites, we did not find a significant difference in fracture rates between these 2 races.
Fractures were found more often in patients with
worsening functional class (class I, 18%; class I1,38%;
class 111, 100%); these differences, however, were not
significant. Since most of our patients (96%) were in
functional class I or 11, we cannot exclude the possibility that in a more disabled population of rheumatic
disease patients, low bone mineral mass due to immobilization could increase fractures.
In summary, certain treatment and patient characteristics are associated with elevated DM:MM ratios
and/or bone fractures in ambulatory rheumatic disease
patients receiving long-term glucocorticoid therapy
(Table 5 ) . Large cumulative doses of prednisone are
associated with elevated DM:MM ratios and fractures.
Age 2 5 0 years or postmenopausal state is associated
with fractures, and many of these elderly patients with
fractures have evidence of glucocorticoid-induced osteopenia (elevation of DM:MM ratio). Although worsening functional class is not associated with a significant increase in fractures, based upon previous reports
(1,2) and trends found in this study, functional class
may be a significant factor. Finally, elevated DM :MM
ratios and fractures occur with similar frequency in
males and females, in whites and blacks, in patients
with different rheumatic diseases, and in those on
different regimens of prednisone.
These findings using DM:MM ratios suggest
that long-term glucocorticoid therapy in various regimens may result in glucocorticoid-induced osteopenia.
This effect is cumulative, occurs in all patient groups,
and results in more fractures in patients 2.50 years of
age, postmenopausal females, and patients receiving
large cumulative doses.
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Seeman E, Melton LJ, O’Fallon WM, Riggs BL: Risk
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75 :997-1003, 1984
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factors, associates, patients, induced, osteopenia, glucocorticoid, rheumatic, evaluation, disease
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