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The early diagnosis of ischemic necrosis of bone.

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arthritis
and
rheumatism
Official Journal of the American Rheumatism Association
THE EARLY DIAGNOSIS OF ISCHEMIC NECROSIS
OF BONE
T. M. ZIZIC, C. MARCOUX, D. S. HUNGERFORD, and M. B. STEVENS
One hundred sixty-nine patients with radiographic or histologic evidence of ischemic necrosis of
bone (INB) were evaluated. Ninety-nine (59%) of the
169 patients had multiple sites of INB, with 310 bones
affected. Two hundred sixty-three (85%) of the 310
ischemic bones were symptomatic. Routine radiography
produced negative findings in 58 (20%) of the bones with
histologically confirmed INB. Results of hemodynamic
studies, including baseline bone marrow pressure, saline
stress test, andlor intraosseous venography, were abnormal in 243 (94%) of 259 ischemic bones so evaluated.
Most importantly, hemodynamic studies detected 51
(93%) of the 55 bones that were radiographically normal but had histologically confirmed INB.
Ischemic necrosis of bone (INB) is an increasingly recognized cause of musculoskeletal disability in
From the Department of Medicine, Division of Rheumatology, and the Department of Orthopedic Surgery, Johns Hopkins
University School of Medicine, Baltimore, Maryland.
Supported in part by USPHS grant 1-RO-1-AM-2079801,an
Arthritis Foundation Clinical Research Center grant, the Good
Samaritan Hospital Endowment Fund, and NIAMD Multipurpose
Arthritis Center grant 1P60-AM-20558-01.
T. M. Zizic, MD: Associate Professor of Medicine; C. Marcoux, MD: Postdoctoral Fellow in Rheumatology; D. S. Hungerford, MD: Associate Professor of Orthopedic Surgery; M. B.
Stevens, MD: Professor of Medicine.
Address reprint requests to T. M. Zizic, MD, the Good
Samaritan Hospital, 5601 Loch Raven Boulevard, Baltimore, MD
21239.
Submitted for publication January 10, 1985; accepted in
revised form March 3, 1986.
young persons. Numerous terms have been used to
describe this phenomenon of dead or dying bone,
including aseptic necrosis, osteonecrosis, and avascular necrosis. Because the bone is truly avascular
only in the end stage of the disease, we prefer the term
“ischemic necrosis of bone,” which emphasizes the
period of ischemia that precedes actual bone death.
Many factors have been considered in the
pathogenesis of this bone condition, in part, because
of the heterogeneous group of diseases that are associated with INB. Ischemic necrosis of bone has been
reported as a complication of trauma, caisson disease,
and multiple systemic diseases, including hemophilia,
hemoglobinopathies, Gaucher’s disease, alcoholism,
pancreatitis, rheumatoid arthritis, and systemic lupus
erythematosus (SLE) (1-20). There is considerable
controversy concerning the pathogenesis of INB. This
is partly due to the lack of a good animal model for the
disease and partly due to the interpretations based on
pathologic changes found in well-established, rather
than early, disease.
Further insight into the pathogenesis of INB
has been derived from the findings by us and by other
investigators, that there is increased bone marrow
pressure (BMP) and/or decreased venous flow in patients with INB, irrespective of radiologic stage
(18-25). Since increased BMP and widespread extraosseous abnormalities are found in preradiologic and
preclinical disease, any postulation of a pathogenetic
mechanism must take these into consideration (19-25).
Arthritis and Rheumatism, Vol. 29, No. 10 (October 1986)
1177
1178
ZIZIC ET AL
It has been suggested that elevated bone marrow
prassure may be a final common pathway in the
development of INB (19-21).
It has been well established that once radiographic changes occur in INB, if the condition is not
treated, most bones involved will collapse, resulting in
severe dysfunction and disability (12,26,27). Although
the treatment of INB is also controversial, nearly all
prdponents of specific treatments agree that the earlier
treatment is begun, the more favorable is the outcome
of treatment (10,18,22,27,28). Therefore, early diagnosis is of paramount importance in this disorder. With
this in mind, we have reviewed our experience with
respect to the critical role of hemodynamic studies in
the early diagnosis of INB and their pathogenetic
implications.
PATIENTS AND METHODS
Patient selection. From March 1 , 1974 until July 1,
1982, 169 patients with INB were admitted on 1 or more
occasions to, and had bone hemodynamic studies performed
at, the Johns Hopkins Rheumatic Disease Unit at the Good
Sarparitan Hospital. The medical records of these patients
wete reviewed in detail according to a predefined protocol.
Particularly emphasized were the diagnostic data obtained
basled on symptoms and clinical evaluation, radiography,
radioisotopic scintigraphy, and hemodynamic studies of the
involved bones.
Diagnosis of INB. Roentgenographic staging of INB
was done according to the criteria of Arlet and Ficat (1,21).
Stage I is a normal roentgenographic result or, at most,
minimal osteoporosis. In stage 11, roentgenography demonstrqtes a normal joint line and head contour with a trabecular
pattern, consisting of patchy osteoporosis and osteosclerosis, often with a wedge-shaped area of sclerosis in the region
of maximal load-bearing. Stage I11 is characterized by a
tradslucent subcortical band appearing as a fine line immediately under the articular cortical bone and parallel to it.
This is the “radiolucent crescent sign” and represents a
fraqture line. Early collapse may be apparent, in which case,
thete may be a widening of the joint space. Stage IV
progression of INB is characterized by a loss of contour of
the bone, which is manifested by either a flattening of a
segbent or a discrete discontinuity (“joint step”), both of
which are caused by further subchondral collapse. With
extensive destruction and collapse, the resultant incongruity
leads to progessive degenerative changes, with marginal
osteophyte formation, narrowing of the joint space, and, in
the hip, secondary acetabular changes. The diagnosis of INB
was confirmed by either stage I1 roentgenographic changes
andor core biopsy and histologic confirmation. In those sites
wi+ preradiologic disease (stage I), histologic Confirmation
was uniformly obtained.
Radioisotopic scintigraphy. Radioisotopic scintigraphy was performed using wmTc-methylene diphosphonate (%“Tc-MDP). Twenty millicuries of 99mTc-MDPwas
injected intravenously. At 2 hours postinjection, anterior
images of the shoulders, hips, and knees were obtained using
a Searle-HP Medex 37 upgrade gamma camera with a low
energy, converging collimator. The camera was set for a
140-keV photopeak with a 20% window. The hips were
placed in maximal internal rotation and imaged for 300,000
counts; the contralateral hip was imaged for the same period.
The shoulders were imaged in the anatomic position for
300,000 counts; the contralateral shoulder was imaged for
the same period. The knees were imaged similarly, but for
100,000 counts. There was simultaneous acquisition of these
images in a digital format on an Ohio Nuclear VIP 450
computer.
To assess the utility of detecting INB by calculating
a target:background (T:B) ratio for each joint, the images
were stored on magnetic tape. Normal T:B ratios were
determined by studying 22 normal hips, 12 normal shoulders,
and 12 normal knees. All of the normal subjects were either
volunteers or were subjects who had scans for peripheral
bone pain, with no abnormal results noted. All of them were
postadolescent and premenopausal. Their T:B ratios were
determined by placing a region of interest (ROI) over the
humoral or femoral heads and over the femoral and tibial
condyles. The background ROI was selected in the proximal
adjacent shaft, not including the epiphysis. The number of
counts per pixel was determined for each ROI, and the ratio
of the T:B counts/pixel was determined. A T:B ratio of 2
standard deviations above or below the mean ratio for the
control population was considered abnormal. We have previously reported further details on our bone scanning techniques (29).
BMP and intraosseous venography. BMP determinations and intraosseous venography were done under local or
general anesthesia, with sterile conditions, and image intensification or biplane radiographic control. A specially prepared rigid needle was inserted percutaneously through the
lateral femoral cortex at the level of the greater trochanter
into the middle of the intertrochanteric area. The obturator
was then removed, the intraosseous needle was filled with
Table 1. Diseases associated with ischemic necrosis of bone
Disease
Systemic lupus erythematosus
Alcoholism
Trauma
Renal transplantation
Asthma
Polymyalgia rheumatica
Hemoglobinopathy
Rheumatoid arthritis
Sarcoidosis
Bell’s palsy
Psoriatic arthritis
Hepatitis
Caisson disease
Gaucher’s disease
Scleroderma
Raynaud’s disease
Miscellaneous diseases
No known underlying disease
(idiopathic)
No. of
patients
(n = 169)
46
19
10
9
5
4
4
3
3
3
2
2
1
1
1
1
24
31
EARLY DIAGNOSIS OF INB
1179
heparinized saline and connected via a 3-way stopcock and
saline-filled semirigid cannulae to a Validyne pressure transducer, and the pressure was recorded on a Soltec pen
recorder. Because initial pressures may vary slightly and
several minutes may be required before a steady reading is
obtained, the recording at 5 minutes is referred to as the
baseline pressure. After baseline pressure measurements
were taken, 5 ml of physiologic saline was injected intraosseously, utilizing the 3-way stopcock to maintain a closed
system for immediate postinjection measurements. A pressure reading, referred to as the stress pressure, was taken at
5 minutes postinjection.
After the intraosseous pressure determinations, the
recording needle was used to inject 10 ml of soluble contrast
media for venography. Roentgenograms were taken at the
completion of the injection and 5 minutes later. Because the
intraosseous injection of contrast media is uncomfortable,
particularly in patients with ischemic necrosis, systemic
analgesia and sedation is necessary if intraosseous
venography is performed under local anesthesia. Other than
the discomfort experienced when injections were accomplished in patients with elevated bone marrow pressures, we
have had no complications with this procedure.
The control patients were studied (with their informed consent) during surgery for other reasons. These
patients had no symptoms or signs referable to the hip or
knee and had normal results on roentgenograms. None of the
controls had SLE, and none were taking corticosteroids.
Normal BMP in the controls was characterized by baseline
pressure of <30 mm Hg and elevation of BMP of <10 mm
Hg in response to the 5 cc saline stress test. We have
previously reported the details of these techniques
(18,20,23).
Data analysis. Statistical analysis was performed in
the Johns Hopkins Multipurpose Arthritis Center Statistical
Core Unit. The percentage of differences were assessed by
chi-square test (1 degree of freedom), corrected for continuity. The differences in the results at various stages of INB
versus the control values, for the baseline pressures and
stress tests, were each tested by one-way analysis of variance F-test (3 df and 40 df). Bartlett’s test of homogeneity of
variances showed that the variances of the respective means
were not significantly different.
Table 2. Manifestations of ischemic necrosis of bone in symptomatic sites*
Site of involvement
Table 3. Radiographic staging of ischemic necrosis of bone, by
site*
Radiographic stage
Site
I
I1
I1I
IV
Hips
(n = 221)
Knees
(n = 45)
Shoulders
(n = 20)
Ankles
(n = 2)
43 (19)
88 (40)
79 (36)
11 ( 5 )
12 (27)
19 (42)
12 (27)
2 (4)
2 (10)
10 (50)
8 (40)
0
1 (50)
1 (50)
0
0
Total
(n = 288)
58 (20)
118 (41)
* Roentgenograms were available for 288 of the 310 involved bones.
See Patients and Methods for details of staging method. Numbers in
parentheses are percentages.
RESULTS
Demography and associated diseases. Of the 169
INB patients, 86 (51%) were female and 129 (76%)
were white. The mean age was 39.7, with a range of
8-86 years. The underlying diseases in these patients
are listed in Table 1. Including the 46 patients with
SLE and the 9 who received renal allografts, 88 (52%)
of the patients received exogenous glucocorticoids
prior to the development of INB. Thirty-one (18%) had
no known underlying disease; their INB was truly
idiopathic.
Clinical evaluation. The 169 patients had a total
of 310 bones that were involved. Ninety-nine (59%) of
the 169 patients had multiple sites of INB. T w o
hundred thirty-four (75%) of the bones involved were
hips, 53 (17%) were knees, 21 (7%) were shoulders,
and 2 (1%) were ankles (talus).
Two hundred sixty-three (85%) of th e 310
Table 4. Diagnostic accuracy of qualitative versus quantitative
scans*
~
Hips
Knees
Shoulders
Pain on motion
(active)
Pain at rest
Night pain
Pain on motion
(examination)
Limitation of
motion
(examination)
205/208 (99)
40/40 (100)
13/13 (100)
119/179 (66)
53/144 (37)
178/197 (90)
26/36 (72)
9/24 (38)
27/40 (68)
3/7 (43)
10113 (77)
132/205 (64)
10/40 (25)
9/14 (64)
5/8 (63)
* Values are the number with the manifestationitotal number of
symptomatic bones (%).
~
Site of ischemic necrosis of bone
Him
Manifestation
13 ( 5 )
99 (34)
Qualitative
scintigraphy
Positive
74/203 (37)
Negative
107/203 (53)
Equivocal
22/203 (11)
Quantitative
scintimetry
Positive
14/27 (52)
Negative
11/27 (41)
Equivocal
2/27 (7)
Knees
Shoulders
Total
11/34 (32)
18/34 (53)
5/34 (15)
6/12 (50)
4/12 (33)
2/12 (17)
91/249 (37)
129/249 (52)
29/249 (12)
9/15 (60)
5/15 (33)
1/15 (7)
9/14 (64)
5/14 (36)
0
32/56 (57)
21/56 (38)
3/56 ( 5 )
* Values are the number with the result/total number tested (%).
See Patients and Methods for description of scan procedures.
ZIZIC ET AL
1180
Figure 1. Normal bone marrow pressure, consisting of a baseline
pressure of <30 mm Hg and less than a 10 mm Hg increase in
pressure at 5 minutes after injection of 5 cc of saline (stress test).
ischemic bones were symptomatic. It should be emphasized that 47 (15%) of the sites of bony involvement were asymptomatic. The most common symptom was pain on active motion or with weight-bearing,
which was present in 260 (99%) of the 263 symptomatic bones. Pain while at rest was a symptom in 151
(67%) of 225 bones, and pain at night, which often
interfered with sleep, was present in 66 (37%) of 177
bones. On physical examination, pain on motion of the
adjacent joint was found in 215 (85%) of 252 bony
sites. Limitation of motion was less frequently
present: 151 (58%) of 261 cases. Interestingly, except
for less frequent limitation of motion of the knees,
these clinical features were fairly consistent when
their presence in hips, knees, and shoulders was
compared (Table 2).
Radiography. Roentgenograms were available
for 288 of the 310 bones, and their results were entirely
normal in 58 (20%) of the 288 bones. All of these 58
sites had histologically confirmed INB (stage I). The
radiographic staging by site of involvement is listed in
Table 3.
Radioisotopic studies. Qualitative radioisotopic
scintigraphy with 99"T~-MDPwas used to evaluate 249
bones. Ninety-one (37%) of the 249 bones were correctly interpreted as positive, and 29 (12%) were
equivocal. One hundred twenty-nine (52%) were
falsely interpreted as negative; they were sites of
histologically or radiologically confirmed INB .
Twenty of these false-negatives were sites of bilateral
involvement, so that although the uptake was symmetric, it was, in reality, increased bilaterally, or if the
uptake was asymmetric, the more severely affected
side made the less involved side look normal by
comparison.
Quantitative radioisotopic scintigrams were
performed in 56 bones that were subsequently shown
to be sites of ischemic necrosis. Thirty-two (57%) of
the quantitative scans were correctly interpreted as
positive, and 3 (5%) were equivocal. Twenty-one
(38%) were falsely interpreted as negative. Four of
these 21 false-negatives were sites of bilateral involvement. The results of both qualitative and quantitative
scintigraphy with respect to the INB site are shown in
Table 4.
Bone marrow pressures. Both baseline BMPs
and stress test results were determined in 259 bony
Table 5. Baseline bone marrow pressures (BMP) and stress test
results in patients with ischemic necrosis of bone (INB) and in
control subjects, by INB stage*
Baseline BMP
INB stage
I
I1
I11
IV
Total
Figure 2. Bone marrow pressure in ischemic necrosis of bone,
showing a
pressure Of 230 mm Hg and more than a lo mm
Hg increase in pressure that is sustained for 2 5 minutes after
injection of 5 cc of saline (stress test).
Controls
No. sites
43
98
76
8
225
14
Mean (range)
45
38
39
28
(15-110)
(14-92)
(8-115)
(15-50)
39 (8-115)
17 (8-28)
Stress test
No. sites
43
96
75
8
222
14
Mean (range)
54
53
55
49
(13-1lOT
(12-112)
(10-130)
(20-95)
54 (10-130)
18 (8-26)
* All values were significantly different from those of the controls,
p < 0.001 by one-way analysis of variance. See Patients and
Methods for description of procedures.
EARLY DIAGNOSIS OF INB
1181
Table 6. Baseline bone marrow pressures (BMP) and stress test
results in patients with ischemic necrosis of bone (INB) and in
control subjects, by INB site*
Baseline BMP
INB site
Stress test
No. bones Mean (range) No. bones Mean (range)
~~
Hips
Knees
Shoulders
Ankles
180
34
14
2
Controls
14
41
32
39
26
(10-115)
(8-78)
(12-80)
(25-26)
17 (8-28)
178
34
13
2
14
54
51
57
75
(12-118)
(10-110)
(20-130)
(70-80)
18 03-26)
* All values were significantly different from those of the controls,
P < 0.001 by one-way analysis of variance. See Patients and
Methods for description of procedures.
sites. In 6 additional sites, only baseline BMPs were
measured. Two hundred twenty-three (84%) of the 265
bones had baseline pressures of 2 3 0 mm Hg or an
elevation of more than 10 mm Hg following the
intraosseous injection of 5 ml of saline (stress test), as
compared with none of the controls (Figures 1 and 2).
Tables 5 and 6 delineate the pressure findings according to the radiologic stage of INB and site of involvement, respectively. There was a highly statistically
significant difference in the mean baseline BMP in all 4
stages of INB, as well as at sites of involvement, when
compared with controls (P< 0.001 by one-way analysis of variance). Similarly, the mean response to the
stress test was highly significantly different for patients
in stage I, 11, 111, and IV, when compared with
controls (P< 0.001 by one-way analysis of variance).
The value of combined baseline pressures and stress
test measures is illustrated in Table 7 and shows that
an additional 48 (19%) of the bones with INB would be
interpreted as being normal if the baseline BMPs were
measured only.
Intraosseous venography. Intraosseous venography was performed in 219 bones with 1NB and in 10
controls. Venography in bones with INB was characterized by various combinations of absent or incomplete filling of the main extraosseous veins, diaphyseal
reflux, and stasis of contrast media, as seen on films
taken 5 minutes postinjection (Figure 3) and on subsequent films. Venography in bones of the controls was
characterized by: 1) rapid filling of the extraosseous
veins; 2) lack of diaphyseal reflux; and 3) complete or
near complete clearing of the dye at 5 minutes
postinjection (Figures 4A and B).
One hundred ninety-three (88%) of the 219 INB
bones studied had 1 or more abnormalities on intraosseous venograms (Table 8). Most importantly, of the
39 patients with normal baseline BMPs and stress test
results (Table 7), 32 had venography performed, and
23 (72%) of these tests showed abnormal results. Thus,
in our experience, hemodynamic studies, including
baseline BMPs, saline stress tests, and intraosseous
venography, correctly identified 243 (94%) of 259
bones with ischemic necrosis.
In the 58 bones with preradiologic disease
(stage I), qualitative scintigraphy was positive in 14
(40%) of 35 bones studied, and quantitative scintigraphy was positive in 8 (73%) of 11 bones studied.
Abnormal results of baseline and/or stress tests were
Table 7. Results of baseline bone marrow pressure (BMP) and
stress tests in patients with ischemic necrosis of bone (INB)*
Results of measurement
Baseline above that of controls, and
stress above that of controls
Baseline above that of controls, and
stress normal
Baseline normal, and stress above
that of controls
Baseline normal, and stress normal
* There were
percentages.
No. of bones with
INB
109 (42)
63 (24)
48 (19)
39 (15)
259 bones evaluated. Numbers in parentheses are
Figure 3. Intraosseous venogram. Left, Abnormal result at termination of injection of soluble contrast material. There is poor filling
of metaphyseal veins, and diaphyseal reflux. Right, Film taken 5
minutes postinjection (same patient), revealing considerable residual dye (stasis).
1182
ZIZIC ET AL
Figure 4. Intraosseous venogram. A, Normal result at termination of injection of soluble contrast material. There is a blush of dye at the tip
of the needle, filling of metaphyseal vessels, and no reflux of dye below the level of the lesser trochanter. B, Film taken 5 minutes postinjection
(same patient), demonstrating nearly complete clearing of dye from the bone.
found in 46 (87%) of 53 sites studied. Venography was
positive in 3 of the remaining 7 bones as well as in 2
additional bones that did not undergo pressure studies.
Thus, baseline BMP, stress tests, and/or venographic
abnlorrnalities were present in 51 (93%) of 55 radiographically normal bones that were evaluated. Overall, hemodynamic studies were significantly more sensitive than scanning techniques in detecting
pretadiologic (early) disease (P < 0.001).
that once radiographic changes have occurred, the
results of nonoperative management alone are not
satisfactory (3,27,30-32).
Unfortunately, the early stages of INB are often
subclinical, or the symptoms are minimal and the
patient does not immediately seek medical attention.
Even more unfortunately, those patients who do seek
Table 8. Venographic abnormalities found in patients with
ischemic necrosis of bone (INB)*
DISCUSSION
Various treatment modalities have been developeP in an attempt to save ischemic bone from ultima+ destruction; however, there is general agreement
thaq, no matter which procedure is chosen, the results
are in large part determined by the stage of the disease
at the time of diagnosis. In many instances, once the
dissase becomes radiologically evident, it is relentlessly progressive and leads to serious joint dysfunction (1 2,26). Similarly, there is considerable evidence
Results of venography
Stasis + reflux
Stasis + reflux + poor venous filling
Reflux + poor venous filling
Reflux only
Stasis only
Stasis + poor venous filling
Poor venous filling
Completely normal venogram
No. of bones with
INB
47
39
33
26
20
19
9
26
(21)
(18)
(15)
(12)
(9)
(9)
(4)
(12)
* There were 219 bones evaluated. Numbers in parentheses are
percentages.
EARLY DIAGNOSIS OF INB
medical attention may not be diagnosed as having INB
because the radiographic findings may be negative, as
was the case in 58 (20%) of the 288 bones with INB
that we studied. Preradiologic disease in these patients
can be diagnosed only if the treating physician has a
high index of suspicion for INB. This condition should
appear in the differential diagnosis of unexplained
pain, particularly in the hips, knees, or shoulders, in a
susceptible host. Patients who have any of the disorders listed in Table 1 are more likely to develop INB,
as are any persons receiving high-dose exogenous
corticosteroid therapy for any reason. A high index of
suspicion should also be maintained in evaluation and
treatment of patients who already have an ischemic
bone. Since 99 (59%) of the 169 patients described
herein had multiple sites of INB, the majority of the
INBs occurred while the patients were under medical
supervision. In fact, it was because of our cognizance
of this that most of the 58 preradiologic bones were
diagnosed.
It is our opinion that the first step in evaluating
such patients is to do radioisotopic scintigraphy if
radiographs of the suspected bones produce negative
findings. Qualitative scans were helpful in positively
identifying 14 (40%) of 35 preradiologic INB bones and
were suggestive in an additional 4 (11%). The relatively high incidence of false-negatives (17 of 35 [49%])
results from the method of interpreting qualitative
scintigraphs, which is generally based upon asymmetric uptake of the radioisotope. In patients with bilateral involvement, interpretation becomes difficult. In
early bilateral involvement which is symmetric, both
bones are often interpreted as negative. In asymmetric
involvement, the less affected side is often overlooked. Some of these problems are obviated by
quantitative scans since one is analyzing the absolute
amount of radioisotope uptake in comparison with that
of normal, control bones (see Patients and Methods).
Consequently, of 11 stage I bones studied by this
technique, 8 (73%) were abnormal. In patients with
early preradiologic disease, approximately 25% of the
bones will be falsely interpreted as negative because
the uptake may not be sufficiently different to fall
outside of 2 standard deviations from the mean value
for normal controls. In our experience, the hemodynamic assay has been determined to be the most
sensitive and valuable tool for the early diagnosis of
INB. A combination of the results of baseline BMP,
saline stress test, and intraosseous venography detected 51 (93%)of 55 bones with preradiologic disease.
Ischemic necrosis of bone, like infarction in
1183
other organ systems, results from a significant reduction in or obliteration of the blood supply to the
affected area (33). Cessation of blood flow may be
initiated in any portion of the vascular network. Three
potential mechanisms have been recognized in the
pathogenesis of INB: 1) interruption of the arterial
input to bone (8,11,12,14-21,34); 2) derangement of
the intraosseous venous drainage, with secondary
arterial insufficiency (20,35-38); and 3) extravascular
intraosseous derangement, with subsequent eventual
compromise to the venous outflow and/or the arterial
circulation (20,39,40). However, there is still considerable controversy as to which of these mechanisms is
the primary or most important part of the pathogenetic
sequence in INB (6,20,41-43). Furthermore, any 1 of
these mechanisms or a combination of them might be
operative in different diseases that are associated with
the development of INB.
The demonstration of elevated BMP and/or
decreased outflow capacity (by venography), which
have been reported previously by us and by others
(18-25,28,31), as well as the findings reported here,
suggest that increased BMP and venous stasis are of
pathogenetic significance in the development of INB.
Of particular significance are their presence in early
disease, before radiologic abnormalities appear, and
even in asymptomatic bones, in which findings of
increased BMP and venographic abnormalities may be
of predictive value (24).
Consequently, we postulate the pathogenetic
sequence for INB depicted in Figure 5. Initial ischemia
can be produced by either extraosseous and/or intraosseous circulatory disturbances. Extraosseous interruption of arterial flow can occur with trauma and
severance of major vessels. Intraosseously , the
sinusoidal microcirculation can be obstructed by
sickled erythrocytes, thrombi, nitrogen bubbles, or
emboli. In this event, ischemia can be produced,
which causes damage to intraosseous cellular components, with resultant edema and elevation of the bone
marrow pressure. The increased bone marrow pressure produces increased resistance and decreased
bone blood flow, resulting in further ischemia, and a
self-perpetuating vicious circle may be initiated.
This pathway may be entered via increased
BMP in situations where the microcirculation is compressed intraosseously . This occurs when abnormal
cells (e.g., Gaucher’s or tumor) accumulate in the
marrow space, expanding nitrogen bubbles occur (in
caisson disease), or as a result of intramedullary
lipocyte hypertrophy (in glucocorticoid-treated pa-
ZIZIC ET AL
1184
EXTRA-OSSEOUS (ARTERIAL)
TRAUMA
VASCULITIS
VASOSPASM
RAYNAUD'S
DECOMPRESSION SICKNESS
INTRA-OSSEOUS
SINUSOIDAL OBSTRUCTION
SICKLED CELLS
THROMBOSIS
NITROGEN BUBBLES (INTRAVASCULAR)
EMBOLI (FAT)
EXTRA-SINUSOIDAL COMPRESSION
GAUCHER'S CELLS
NITROGEN BUBBLES (EXTRAVASCULAR)
TUMOR
LIPOCYTE HYPERTROPHY
CELLULAR DAMAGE
I
V
I
f i e
BONE NECROSIS
C0l"LNn"PSE
RESISTANCE
n
\\
\BLOOD FLOW
I WFIGHT-BEARING
EXTRA-OSSEOUS (VENOUS)
Figure 5. Postulated pathogenesis of ischemic, or avascular, necrosis of bone, The etiology is multifactorial, with
numerous conditions that may act independently or in concert. Bone marrow pressure may be elevated directly or via
ischemia, with resultant cellular damage and edema. The final common pathway appears to be increased bone marrow
pressure, which produces increased resistance to flow and ischemia, with subsequent cellular damage and edema, which
leads to a further elevation in the intraosseous pressure. If uninterrupted, this vicious cycle results in bone necrosis and
collapse, particularly with continued weight-bearing.
tients). Once the vicious circle is entered in the weightbearing area of the bone, increased compression of the
microcirculation by the transmitted pressure of loadbearing accentuates the problem. The subchondral
bone just beneath the cartilage is denser than are the
deeper layers, and the pressure is transmitted to the
latter, producing another amplification loop that, in
most cases, eventuates in bone necrosis and collapse.
Additional evidence supporting this postulated pathogenetic sequence comes from the results of core
decompression, which not only may provide rapid
relief of symptoms, but may arrest the disease if done
early enough (18-22,27,44).
In summary, hemodynamic studies, in our experience, have been a safe, simple, and sensitive
method for diagnosing INB. These techniques provide
an all ernative to radiography, tomography, and
scintigraphy, which are noninvasive but are not as
sensitive for early detection of INB. Our experience
has demonstrated that increased bone marrow pressure and altered venous drainage are characteristic of
all stages of INB, including the preradiologic state. If
abnormal, they have significant predictive values for
those bones that are likely to become ischemic. Our
results also suggest that BMP elevation is at least an
early, if not the primary, factor in the pathogenesis of
INB. Acceptance of this pathogenetic sequence
should lead to more intensive investigation of the
patient suspected of having early INB and a more
hopeful attitude toward the management of those
cases detected early.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to Dr.
Marc C. Hochberg and V. Kosmides of the Johns Hopkins
MAC Statistical Core Unit for their assistance in data
analysis and B. Kelley for preparation of the manuscript.
EARLY DIAGNOSIS OF INB
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