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Osteoporosis of rheumatoid arthritisInfluence of age sex and corticosteroids.

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Osteoporosis of Rheumatoid Arthritis :
Influence of Age, Sex and Corticosteroids
By PAULD. SAVILLEAND OVEDKHARMOSH
S
The cortical thickness of the left radius just below the tuberosity was measured by the method
of Meema.4 Standard lateral roentgenograms of the
thoracic and lumbar spine were taken. All the
roentgenograms were read by one of us without
prior knowledge of the age or sex of the patient or
any clinical data. The lateral lumbar spine was
evaluated for bone density in 4 categories. In
order to make these judgments, we took into consideration the quality of the trabecular pattern
with increased vertical striation, loss of density
compared to soft tissues, and thinness of the upper
and lower plates of the vertebral bodies. Vertebral
fractures were ignored on this assessment and were
considered on a separate basis. The four categories
are:
Grade 0: normal bone.
Grade 1: minimal loss of bone density; the
end plates begin to stand out, giving
a stencilled effect.
Grade 2: vertical striation is more obvious; the
end plates are now thinner.
Grade 3: more severe loss of bone density than
grade 2; the end plates are becoming
less visible.
Grade 4: ghost-like vertebral bodies; density
is no greater than soft tissue. No
trabecular pattern is visible (when
the vertebral outline is covered, the
body is invisible).
Clinical data were recorded on self-coding data
sheets from which cards were punched. The cards
were sorted in various ways for purposes of the
analysis. The statistical characteristics of the
grading system used, its reproducibility among
physicians and its properties consistent with the
osteoporosis is an integral part of
Cushing's syndrome,l it is commonly
assumed that the osteoporosis and vertebral fractures seen in patients with rheumatoid arthritis who are treated with corticosteroids are mainly due to the drug. Actually, there are 2 separate bone entities
which require assessment and which may
not be directly related one to another; first,
osteoporosis or decreased bone mass, and
second, compression fractures of the spine.
Either or both might be influenced by
treatment.
It is the purpose of this paper to assess
the influence of age, sex, and severity of
disease as well as of corticosteroid treatment on the osteoporosis of rheumatoid
arthritis and on the incidence of compression fractures of the spine.
INCE
METHODS
The patients were from a consecutive series
who were selected from the Rheumatic Disease
Clinic of The Hospital for Special Surgery because they had been diagnosed by the attending
physicians as suffering from rheumatoid arthritis.
There were 128 women and 36 men. Although
the ARA criteriaa were not formally applied to
each case, they were used as a basis for making
the clinical diagnosis. Functional status was classified according to Steinbrocker, Traeger and Batterman?
From The Hospitd for Special Surgery asliated
with The New York Hospital-Cornell University
Medical Center, New York.
This investigation was supported in part by
Public Health Service Research Grant No. 5 SO1
Fr-05495 from the General Support Branch Division of Research Facilities and Resources; 1 PO1
AM 09982-01 of the National Institutes of
Arthritis and Metabolic Diseases and U.S.P.H.S.
Graduate Training Grant TIAM-5414 of the National Institutes of Arthritis and Metabolic Diseases.
PAUL D. SAVILLE,M.D.: Associate Professor of
Medicine, Cornell University Medical Center; Associate Attending Physician, The Hospital for
Special Surgery; Associate Attending Physician,
New York Hospital; Senior Scientist; Chief,
Metabolic Bone Disease Clinic and Associate
Director of Research-The Hospital for Special
Surgery. OVED KHARMOSH,M.D.: Orthopaedic
Fellow. Present address: Department of Orthopaedics, Zchilov Municipal Hospital, Tel-Aviv,
Israel.
423
ARTHRITIS AND RHEUMATISM,
VOL. 10, No. 5 (October 1967)
424
SAVILLE AND KHARMOSH
Table 1.-Distribution
______
of Corticosteriod Dose Among Rheumatoid Patients
-__
Number of patients
Dose of
prednisone
Females
Zv5 - 10 mg.
12U.;. - M mg.
22?/1- 30 mg.
>30 mg.
46
Males
7
2
1
For example, it is apparent that in both
men and women there are significantly
RESULTS
more individuaIs in the severer grades of
osteoporosis among those over 50 than
Influence of Age and Corticosteroids
Of the patients who were given corti- among those under 50. This is equally true
costeroids, almost all took prednisone. Dis- for those treated with corticosteroids as for
tribution of dose among the corticosteroid those untreated. This striking finding s u g
treated patients is given in Table 1 in gests that age has a more important effect
terms of prednisone. We have reported the on spinal osteoporosis than does corticosttypical dose schedule indicated in the pa- eroid treatment, as used in our clinics. It
tient’s records. We have not taken into ac- accounts for the small number of younger
count short periods of higher dose that may women and men with moderate or severe
have been given on occasions, nor have we osteoporosis, as shown in Tables 2 and 3.
The insufficiency of cases of osteoporosis
considered that the patients may have
taken amounts of the drug other than that among the younger age groups is thus a
natural one, and makes it necessary to comprescribed and reported in the charts.
Fig. 1 indicates that the average cortical bine mild, moderate and severe grades in
thickness of the radius is similar in women order to compare men and women under
who were given and those who were not 50 with respect to treatment with steroids.
given corticosteroid treatment until the The result may be read from Tables 2 and
sixth decade; at this time the cortical thick- 3 and is described as follows:
For men no significant effect of steroid
ness decreases in those treated; in subsequent decades both treated and untreated treatment on grades of porosity is found
groups decrease, the decrease being great- for those under 50 years (P>O.2); but
er in those receiving corticosteroid treat- such an effect is significantly present in
ment. In men, aIthough average corticaI those over 50 (.Ol>P>.OOl). These tests
thickness was less in the sixth decade, there are necessarily performed by combining
was a decrease in cortical thickness in the grades, as described above.
For women under 50 years, a steroid
sixth decade in both treated and untreated
groups (Fig. 2 ) . There was a tendency for effect on severity of grades is barely dis(grades being
it to increase again in both groups with cernible (O.l>P.>OS)
succeeding decades; differences between combined as above). In the case of women
those men taking corticosteroids and those over 50, however, with sufficient cases
present to test a division of grades into
not were insignificant.
Table 2 shows how spinal porosity va- normal, mild and moderate/severe, a
ries in women given corticosteroids com- significant interaction between steroid
pared to those not given them. Table 3 pre- treatment and grade of osteoporosis is
sents the same breakdown for the men. found (.OZ>P.>OS).
These tables may be read in several ways.
It is of interest to note that adding all
normal distribution ha:: been described elsewhere?
425
OSTEOPOROSIS OF RA: INFLUENCE OF AGE, SEX, CORTICOSTEROIDS
Table 2.-Grades of Spinal Osteoporosis in Female Rheumatoid Patients
Porosity
N o steroids
Steroids
Under 50 years:
Normal
Mild
Mod./sev.
Over 50 years:
16
2
1
7
xam
7
0
P
Norma1
2.99
> .2
I
8
24
20
Mild
Mod./sev.
1=
Xaw = 6.61
.02 P .05
17
> <
25
~-
7 1
6
Fig. 1.-Shows
the
average cortical thickness of the radial shaft
in 128 women at each
decade from the third
both for those treated
with
corticosteroids
and those not so
treated.
5
2
21-30
31-40
41-50
51-60
61-10
11-60
81-90
AGE GROUPS IN YEARS
Fig. 2.-Shows
the average cortical thickness of the
radial shaft in 36 males at
each decade from the f3th
decade both for those treated
with
corticosteroids and
those not so treated.
P I - 50
51-60
61-10
AGE GROUPS IN YEARS
11-80
426
SAVILLE AND KHARAZOSH
Table 3.--Grades of Spinal Osteoporosis in Male Rheumatoid Patients
--
__.____--
;Lo steroids
Porosity
_-Under SO ?tmr.s:
Kormal
Mild
Lfotl.Jsev
Orrrr 50 ?'c-</l..i:
Normal
Mild
MOd./W\
__
~
_____..____
Steroids
~ _ _ _
~-
~-
X",, = 2.57
P > .2
2
~-
2
1
0
2
7
5
2
0
7
x2a,= 7.77
.01
1
__
.~
--__~
> P > ,001
~~_____
Table 4.-Analysis of Covariance of the Regressions of Cortical Thickness of the
Radius vs. Age in Female Rheumatoids Treated for Varying Lengths of Time with
Corticosteroids
~-
.~
P Value
2; Ratio
scatter
slope
means
scatter
slope
means
*
-__
>.2
>2
>.2
1.07
0.58
37
1.5
.97
7.34
.08
Significxit0+1>2.
,135 mni.
Not
significant
.77 mm.
.75
.05>P>.Ol
P>.2
P>.2
scatter
slope
mcans
5.0
29
3.5;
.OS>P>.Ol
P>.2
.1 >P>.O5
1.06
9.22
-
scatter
slope
means
1.34
Not
significant.
.85 mm.
5.O
scatter
slope
means
iiim.
__
Comments
.2>P>.1
>.2
<.01 P<.001
scattct
slope
means
1.16
- ______
Difference between
means/slopes
.01
.45
.32
Suggestive-
P>.2
P>.OO1
-
.06
P>.2
.2
.2
>
>
4
> 2.
Significant4 steeper
than 3.
.23 mni.
.-
0 = no corticosteroid treatment
1 =less than 1 year
2 = 1-13 years
3 = 2-5 years
1=more than
I:
years.
male and female cases under 50 years still
fails to provide significant evidence for a
steroid-porosity relationship in these
younger cases.
Durufion of Treatment
In women, since cortical thickness of the
radius decreases linearly with age after 50
(Fig. l ) , we have compared the regressions of cortical thickness versus age after
50; these regressions were then compared
among the various treatment groups by analysis of covariance (Table 4).These analyses showed no significant difference hetween women not treated with corticosteroids compared to those treated for less than
427
OSTEOPOROSIS OF RA: INFLUENCE OF AGE, SEX, CORTICOSTEROIDS
ment affects spinal osteoporosis in women.
There were greater numbers in the higher
grades of spinal porosity among women
treated with corticosteroids for more than
one year, compared to those not treated or
treated with corticosteroids for less than
one year. In men, the number of cases in
each grade was insufficient for chi square
testing. However, we were able to compare the cortical thickness of the radius in
men not treated with corticosteroids com0 ' " " " " ' ' ~
20
M
40
50
60
70
pared to those treated for more than one
Age lyearsl
year. Again, no significant differences were
Fig. 3.-Regression
of radial cortex thick- shown between the groups.
ness versus age in women treated for one to
five years compared to those treated for more Functional Disability
than five years with corticosteroids. The lines
Fig. 4 shows that in general the average
best fitting these points were calculated by the
cortical thickness of the radius decreases
method of least squares.
with increasing grades of functional disone year. There was, however, a significant ability both in men and in women. Table
difference between these two groups com- 6 shows how spinal porosity grades genbined compared to those treated for 1 to eraLly increase with increasing functional
2 years, 2 to 5 years, or more than 5 years disability in women.
0
Females treated lor more than 5 years with corticosteroids
* Females h a t e d for 1 t o 5 years with corticosteroids
respectively. The three groups of patients
treated for more than one year had thinner
radial cortices than women untreated or
treated for less than one year.
There was no difference in cortical thickness when women treated for 1 to 2 years
were compared to those treated for 2 to 5
years. In women treated for more than 5
years with corticosteroids, the rate of loss
of cortical thickness with age was significantly greater than in those treated for
less than 5 years. This difference resides
in the decrement of cortical thickness with
increment of age, which is greater for those
women treated for more than 5 years. This
slope difference, however, could be attributed not to the presence of a thinner
radial cortex in older women treated with
corticosteroids, but rather to a thicker radial cortex in the younger women treated
for more than 5 years, suggesting that corticosteroids may have a protective effect on
cortical bone in younger women (Fig. 3 ) .
Table 5 shows how the duration of treat-
Spine Fractures
Compression fractures of the spine occurred in 16 women, all of whom were
over the age of 50, and 3 men, one of whom
was over 50. These overall figures may be
broken down as follows: of 52 women who
were not treated with corticosteroids, 9
(16.3 per cent) had compression fractures
of the spine, while of 42 women given corticosteroids, 7 (16.6 per cent) had compression fractures of the spine; the difference
is obviously not significant.
DISCUSSION
Bradley and Ansell,6 observing 216 patients with Still's disease, found that in 63
maintained on steroids for 3 months or
longer, 5 developed vertebral fractures,
compared with 2 out of 153 patients who
had a shorter or no steroid therapy. On the
other hand, Iong bone fractures were
equally common in both groups. These
authors concluded that patients with Still's
428
SAVILLE &ID, KHARMOSH
Table 5.-The
Effect of Treatment with Steroids on Spinal Osteoporosis in Female
Rheumatoid Patients
Steroids
Spine porosity
1
2
3
6
26
9
6
1
1
1
1
4
4
1.5
7
8
3
3
0
24
None
1 year
1-2 years
2-5 years
> j years
-
Xam = 8.045
.02 P <= .05
Xaw:=1.389
P >.2
Xam = 4.892
.1 P
.2
I. None vs. all treated
<
< 1 year
< 1 year vs. > 1 year
11. None vs.
111.
7
< <
3
-
Significant.
Not significant.
Not significant.
vertebral fractures, while none in the 36
not so treated sustained such fractures.
These authors remarked that the difference
could have occurred by chance alone.
Our findings confirm that the incidence
of spinal compression fractures in rheumatoid patients treated with corticosteroids in
*...
....
....
....
... the dosage reported here is no greater than
....
... in patients who have not received corticosteroids. Furthermore, an overall inci....
....
...
....
... dence of spine fractures of 16 per cent in
....
...
....
... arthritic women between SO and 75 years
....
...
of age can be compared to the incidence
....
...
....
... found
...
in normal women by Smith and
....
...
....
Frame.8 These authors, examining 2,063
I
2
I
women seen in routine health examinations,
IUN:TIDNAL STATUS
found an incidence of wedging or compresFig. 4.-Shows the average cortical thick- sion fracture of the vertebrae increasing
ness of the radial shaft in men and women from 6.8 per cent in the groups from 60 to
against grades of functional status.
64,and 11.5 per cent for those from 65 to
69,
to 20.3 per cent for women 70 to 74
disease, especially females contracting the
years
old. The incidence found in our padisease before 5 years of age, are especially
tients
would seem to fall within this range.
prone to osteoporosis and fractures and
It
is
also
clear that while corticosteroids inthat this is uninfluenced by corticosteroid
crease
the
incidence and seventy of osteotreatment. McConkey and his associates7
porosis,
they
do so significantly in this
examined 97 patients with rheumatoid
series
only
in
patients
over the age of 50;
arthritis and found osteoporosis in 28 per
and
in
men,
only
the
spine seems to be
cent riot treated with corticosteroids and
affected.
We
have
failed
to show an ad33 per cent treated with them. This difference was not significant. However, 5 cases verse effect of small doses of prednisone on
out of 61 in the treated group sustained spine density in men and women under
.::.....
Itmale
o . . .
I..
,
I
.
.
I
.
.
.
429
OSTEOPOROSIS OF RA: INFLUENCE OF AGE, SEX, CORTICOSTEROIDS
Table 6.-Steinbrocker’s
Classification on Spinal Osteoporosis in Female
Rheumatoid Patients
~
Classification
1 Mild, no disability
2 Moderate, some disability
3 Severe, disabled
4 Crippled, confined
lvs.2f-3i-1
Spine porosity
0
1
2
3
11
19
2
41
1
32
2
1
9
-
the age of 50. Furthermore, we have shown
that cortical thickness was greater in the
sixth decade in women treated for more
than 5 years with prednisone than it was
in women treated from 1 to 5 years. This
suggests that in women under 50, it is possible, with small disease-suppressing doses
of prednisone, to steer the patient between
the Scylla of rheumatoid-induced osteoporosis and the Charybdis of prednisone-induced osteoporosis.
As regards the duration of treatment
with corticosteroids, the spine data suggest,
and the radial cortex data confirm, that
steroids exert a measurable effect on bone
density after more than one year of treatment and that this effect is not progressive
with time.
Castillo and associates9 evaluated hand
radiographs for cystic changes and osteoporosis and found that cystic changes were
more common and osteoporosis uncommon
in men, especially manual workers, while
the reverse was true for women; cysts were
uncommon and osteoporosis more common.
These authors attributed the greater degree of osteoporosis in women to lack of
physical activity, while the cysts and lack
of osteoporosis in men they ascribed to increased activity in laboring men. Our data
show that both cortical thickness of the
radius and spinal porosity are significantly
related to the degree of disability both in
men and women. Whether this effect is
attributable to disuse or in some other way
to the rheumatoid processlo is uncertain.
5
1
Xats>=22.843 P <.001
-
-
However, it is clear that women have more
osteoporosis than men because of a sudden
change, presumably the menopause, which
occurs in the sixth decade. While small
doses of corticosteroids have been shown
to play a role in the development of osteoporosis, age, sex and physical disability are
more important.
SUMMARY
Osteoporosis has been evaluated from
roentgenograms of the lumbar spine and
left radius in 164 patients suffering from
rheumatoid arthritis. Osteoporosis was a
common finding in men and women whether treated with corticosteroids or not, especially in women over 50. Corticosteroids
given in the dosage schedule reported here
increased the osteoporosis of the spine in
both sexes, mainly over the age of 50; the
radial cortex became thinner on corticosteroids in women over 50 but not men,
and this effect was observed after more
than one year on treatment, but it was not
progressive. Spine fractures occurred in 16
per cent of women, all of whom were over
50; the incidence was not greater in those
patients treated with corticosteroids nor
was it much greater than in normal North
American women of comparable age reported in the literature.
ACKNOWLEDGEMENT
We would like to thank Dr. Melvin S. Schwartz,
Laboratory of Biornetrics, The Hospital for Special
Surgery, for statistical advice and computational
assistance.
430
SAVILLE AMJ KIIARMOSI-I
SUMMARJOIN INTERLINGUA
Esseva effectuate un evalutation del osteoporose in 165 patientes rheumatoide a base
de radiographias spinal e cubital. Osteoporose esseva presente a plus alte nivellos de
incidentia in feminas de plus que 50 annos de etate, sin reguardo a si o lion illas habeva
recipite corticosteroides. U n augment0 significative de osteoporose esseva causate per
corticosteroides solo in masculos e femininas d e plus q u e 50 annos de etate e post plus
q u e u n anno de tractamento. Le incidentia de fracturas spinal esseva 16 pro cento in
feminas tractate con corticosteroide e in feminas non tractate con corticosteroide. Le
parametros del etate, del sexo, e del morbiditate mesme exerce u n plus importante
influentia super l e osteoporose q u e micre doses de corticosteroide.
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2. Ropes, M. W., Bennett, G. A., Cobb, S.,
Jacox, R. and Jessar, A. R.: Diagnostic
criteria for rheumatoid arthritis-1958 Revision. Ann. Rheum. Dis. 18:49,1959.
3. Steinbrocker, O., Traeger, C. H., and Batterman, R. C . Therapeutic criteria in
rheumatoid arthritis. J.A.M.A. 140:659,
1949.
4. Meema, H., Meerna, S.: Measurable roentgenologic changes in some peripheral bones
in senile osteoporosis. J. Amer. Geriat. Soc.
11:1170, 1963.
5. Saville, P. D.: A quantitative approach to
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6. Bradley, B. W. and Ansell, B. M.: Fractures
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9.
10.
in Still's disease. Ann. Rheum. Dis. 19:135,
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McConkey, B., Frazer, G. M., and Blight,
A. S.: Osteoporosis and purpura in rhenmatoid disease; prevalence and relations to
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Med. 31:419, 1968.
Smith, R. W. Jr. and Frame, B.: Concurrent
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relation to calcium consumption. New.
Eng. Mecl. 273:73, 1965.
Castillo, B. A., El Sallab, R. A., and Scott,
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osteoporosis in rheumatoid arthritis. Ann.
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Duncan, H., Frost, H. M., Villanueva, A. R.
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