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Long-term osteopenic changes in cancellous bone structure in ovariectomized rats.

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THE ANATOMICAL RECORD 2361433-441 (1993)
Long-Term Osteopenic Changes in Cancellous Bone Structure in
Ovariectomized Rats
S.C. MILLER AND T.J. WRONSKI
Division of Radiobiology, School of Medicine, University of Utah, Salt Lake City, Utah
(S.C.M.); Department of Physiological Sciences, College of Veterinary Medicine, University
of Florida, Gainesville, Florida (T.J.W.)
ABSTRACT
Cancellous bone mass decreases following ovariectomy in
rodents, providing a useful model for post-menopausal bone loss in humans. This study describes and quantifies the longer-term changes in cancellous bone structure in the ovariectomized (OVX) rat. Rats were OVX or
sham-OVX at 100 days of age and bones were collected 540 days later.
Lumbar vertebral bodies were prepared for microradiography and structural analyses (nodal analyses and star volume analyses) of cancellous
bone. Proximal humerii were prepared for scanning electron microscopy
(SEMI. Microradiography confirmed the loss of cancellous bone from the
central spongiosa regions of the vertebral bodies and the humerii in the
OVX rats. Changes in trabecular structural elements included relative increases in the number of free to free, cortical to free, cortical to node struts
and decreases in the node to node struts in the OVX animals compared with
controls. There were increases in average lengths of the node to free, node
to node, and free to free trabecular struts in the OVX animals. The marrow
star volume was increased in the OVX animals indicating a greater trabecular separation in these animals compared with controls. Viewed by SEM,
metaphyseal trabeculae in the controls consisted of rods and plates but in
the OVX animals the remaining trabeculae were mostly longitudinal rods
with smaller transverse connecting rods. The remaining bone in the OVX
animals was found in the lateral metaphyseal areas and is consistent with
maintenance of the structural capacity of the bone. These long-term
changes in cancellous bone structure are likely due to the continuation of
functional skeletal loading but a decrease in gonadal hormones resulting in
a decreased necessity to maintain a skeletal mineral store for reproduction
(e.g., pregnancy and lactation). o 1993 Wiley-Liss, Inc.
Key words: Bone, Cancellous bone, Osteopenia, Ovariectomy, Morphometry, Rats
Osteoporosis is a disease characterized by a decrease
in bone mass (osteopenia), strength and functional capacity resulting in fractures and skeletal pain (Alioa et
al., 1985). The primary determinants of skeletal
strength are bone mass and the organization and structure or local architecture of the osseous tissues. The
possible relationship of the structure of cancellous bone
with mechanical competence of this tissue was noted by
Arnold et al. (1966) who observed that during aging of
human bone there were perforations of individual bone
spicules resulting in the loss of connectivity between
trabeculae. It was also observed that as plate-like trabeculae became perforated, there was a successive remodeling into more rod-like structures (Arnold, 1980).
It was proposed that structural changes in the trabecular lattice may result in a greater decrease in bone
strength than would be predicted solely from bone
mass measurements (Bell et al., 1967). More recent
experimental studies have confirmed the relationship
0 1993 WILEY-LISS, INC.
between changes in cancellous bone structure and
strength (Kleerekoper et al., 1985; Mosekilde et al.,
1987).
Gonadal hormones have substantial influences on
skeletal metabolism. For example, the decline in skeletal mass after the cessation of ovarian function in humans is well recognized (e.g., post-menopausal osteoporosis).Estrogen replacement is a common therapy
to slow the rate of bone loss in oophorectomized or postmenopausal women. Bone loss also occurs in rodent
models of gonad hormone deficiency. The ovariectomized (OVX) rat, for example, is a very useful model,
replicating many events associated with the develop-
Received October 28, 1992; accepted December 29, 1992.
Address reprint requests to Dr. Scott C. Miller, Division of Radiobiology, Building 586, University of Utah, Salt Lake City, UT 84112.
434
S.C. MILLER AND T.J. WRONSKX
ment of post-menopausal osteoporosis in humans
(Kalu, 1991). Following OVX in rats there is a rapid
decrease in cancellous bone mass, particularly evident
in the metaphyseal regions of the long bones (Wronski
et al., 1985,1986; Turner et al., 1988; Kalu et al., 1989;
Miller et al., 1991). This initial phase of rapid bone loss
is associated with increased bone turnover (increases
in bone formation and resorption), but with an excess
in bone resorption resulting in a decreased cancellous
bone volume, similar to the perimenopausal period in
humans (Stepan et al., 1987; Wronski et al., 1986,
1989b).At later times after OVX, cancellous bone volume continues to decline, but at a slower rate (Wronski
et al., 1989a,b).There are also corresponding decreases
in the bone turnover rate over those observed early
after OVX.
This study describes and quantifies structural characteristics of cancellous bone in aged rats that were
ovariectomized as young adults. This was done to determine the long-term structural changes in cancellous
bone that occur in the absence of ovarian hormones.
The results from this study demonstrate that 1.5 years
after OVX, in addition to substantial differences in
cancellous bone mass, there are substantial changes in
cancellous bone structure. These changes may reflect
the maintenance of mechanical properties on the bone
in the absence of ovarian hormones.
MATERIALS AND METHODS
Experimental Design
Twenty-four female Sprague-Dawley rats (Charles
River Co., Cambridge, MA) were obtained at 85 days of
age. The animals were caged individually in a room
with a 13 hours on and 11 hours off light/dark cycle.
They were weight randomized into experimental and
control groups. At 100 days of age, 12 animals were
ovariectomized (OVX) and the other 12 were shamOVX using the dorsal approach (Waynforth, 1980)
while under ketasetlxylazine anesthesia. To minimize
the increase in body weight associated with OVX
(Wronski et al., 1987), the food consumption of OVX
rats was restricted to that of the control rats (pairfeeding). The animals were fed a standard rodent chow.
The same number of control and OVX rats was
scheduled for sacrifice at 540 days post-OVX. Some animals died from mammary tumors, renal calculi and
respiratory infections, therefore, the sample size at 540
days post-OVX consisted of 7 controls and 10 OVX rats.
Tissue Preparation
At 540 days after OVX, the animals were killed and
the lumbar vertebral bodies and humerii were collected. The lumbar vertebral bodies were fixed in 70%
ethanol and further dehydrated in absolute ethanol.
The vertebral bodies were separated a t the intervertebra1 disks and embedded individually in methyl methacrylate. One vertebral body from each animal was cut
in the sagittal plane and another cut in cross-section
using a bone saw. The sections were ground to 100 (*m
in thickness and microradiographed. One humerus
from each of the OVX and sham-OVX groups was also
prepared for microradiography. In this case the humerus was cut in the sagittal plane.
N-N
F-F
Fig. 1 . Diagram illustrating the types of bone “struts” determined
by image analysis. The intersection of the various types of struts are
termed “nodes.”The types of struts include cortical node to free end
(C-F), cortical node to node (C-N),node to free end (N-F), node to node
(N-N), and free end to free end (F-F).
Image Analysis
One sagittal section microradiograph and two crosssection microradiographs taken in the middle of the
lumbar vertebral bodies from each animal were selected for trabecular structural analyses. Using a television microscope image analysis system (KSS Scientific Consultants, Magna, UT) interfaced with a
microcomputer, as previously described (Miller et al.,
1989), the entire cancellous bone areas in the crossand longitudinal-sections of the lumbar vertebral bodies were quantified. Using commercial software (KSS
Scientific Consultants), the structure of the cancellous
bone was quantified by “nodal analysis” and “star volume analysis.”
Nodal analyses are useful for defining the connectivity and structure of bone spicules in spongiosa regions
from 2 dimensional images (Garrahan et al., 1986;
Compston et al., 1987), such as from microradiographs.
The microradiographs are captured from the television
microscope image analysis system and converted to binary form. The areas to be quantified (using both the
nodal analysis and star volume software) are selected
and the bone image is skeletonized, obtaining the symmetrical axis, as previously described (Compston et al.,
1989). The symmetrical axis is used to identify the trabecular patterns, or “struts” based on the connections
of these struts with other struts a t “nodes” or free-ends.
The following types of struts are defined, as illustrated
in Figure 1, free end to free end (free-free), node to free
end (node-free),node to node (node-node),cortex to free
(cortex-free),and cortex to node (cortex-node).The data
CANCELLOUS BONE IN OVARIECTOMIZED RATS
Fig. 2. Microradiographs. a: Cross section of the lumbar vertebral body from a control, non-ovariectomized rat. x 18. b: Cross section of the lumbar vertebral body from an OVX rat. x 18. c: Longitudinal
section of the lumbar vertebral body from a control rat. x 10. d Longitudinal section of the lumbar
vertebral body from an OVX rat. x 10.e: Sagittal section of the proximal humerus from a control rat. x 8.
E Sagittal section of the proximal humerus from an OVX rat. x 8.
435
436
S.C. MILLER AND T.J. WRONSKI
Fig. 3. SEM of the proximal humerus from an OVX rat. Little, if any, cancellous bone is found in the
central region of the metaphysis (M). The remaining trabeculae are found in the lateral regions (arrowheads). E, epiphysis. GP, growth plate. X 15.
Fig. 4. Proximal humerus from a control animal. Compared with the OVX animals (Fig. 3), there is
considerable cancellous bone in the metaphyseal region. There is less cancellous bone in the central
metaphyseal region than in the lateral region in these aging animals. X 15.
are expressed as the percent of each strut type. The
length of each strut was also quantified and is expressed as the average length. Changes in the distribution andor the lengths of each type of strut are not
only indicators of trabecular connectivity but also cancellous bone architecture.
Star volume analyses are useful in measuring the
separation between trabeculae in spongiosa regions
(Vesterby et al., 1989).The marrow star volumes were
obtained from the same binary images of the microradiographs as described above for the nodal analyses of
the cancellous bone. Marrow star volumes are defined
as the mean volume calculated from computer-generated lines emanating from a point in the marrow in all
directions to cancellous bone boundaries. If any of the
lines intersect an artificial boundary, such as the edge
of the field, the entire volume was excluded. Marrow
star area measurements were taken in a uniform pattern of points over the spongiosa regions. The average
marrow star volumes measured from each sampling
point, were measured in 2 dimensions, as areas but
were converted to volumes and expressed as mm’. Increases in the size of the marrow star volumes, and
thus the marrow space between trabeculae is considered as an indicator of the removal or perforation of
trabeculae.
Scanning Electron Microscopy
All but one proximal humerii from each group were
trimmed open and rendered anorganic by treatment
with 5%sodium hypochlorite (commercialbleach). This
dissolved all organic material, including the marrow,
exposing the mineral surface of the osseous tissues.
The specimens were dehydrated in ethanol, critical
point dried, coated with gold, and viewed in a JEOL
JSM-35 scanning electron microscope at an accelerating voltage of 20 kV. The scanning microscopy of the
metaphyseal spongiosa was done to assess the threedimensional changes in bone structure and to correlate
these changes with the indices of bone structure obtained from two-dimensional microradiographic images used for morphology and structural analyses.
RESULTS
Microradiography
At 1.5 years after ovariectomy, there were substantial differences in cancellous bone amount and structure at an axial skeletal site (lumbar vertebral body)
and an appendicular site (proximal humerus) (Fig. 2).
There were reductions in the amount of cancellous
bone in the OVX animals, consistent with previous
studies using ovariectomized rodents (reviewed in
437
CANCELLOUS BONE IN OVARIECTOMIZED RATS
TABLE 1. Type and length of trabecular struts in
longitudinal- and cross-sections of the lumbar
vertebral bodies from aged control and OVX rats
Longitudinal-sections
Control
ovx
Type of strut (% of total ? SD)
Free-free
6.4 2 4.2 14.8 2 8.4**
Node-free
37.9 t 8.3 38.9 t 4.6
46.5 t 10.8 26.9 t 9.l****
Node-node
Cortex-free
2.6 f 0.9 5.2 t 3.1**
Cortex-node
8.1 t 2.2 14.1 2.1****
Length of strut (pm 2 SD)
102 f 27 125 t 20*
Free-free
117 t 12 137 t 15****
Node-free
211 k 8
278 2 29****
Node-node
250 2 54 224 ? 27
Cortex-free
161 f 44 196 2 42
Cortex-node
*
Cross-sections
Type of strut (% of total ? SD)
3.6 f 1.9
Free-free
27.8 6.9
Node-free
49.3 t 6.0
Node-node
2.1 1.2
Cortex-free
Cortex-node
17.2 2 5.7
Length of strut (pm f SD)
130 60
Free-free
134 f 27
Node-free
Node-node
241 t 59
Cortex-free
232 44
163 t 25
Cortex-node
*
*
*
Group
Cross-sections
Contro1
ovx
Longitudinal sections
Control
ovx
Marrow star volume
(mm3 SD)
*
0.110 0.069
0.948 f 0.714*
0.249 2 0.126
1.419 ? 0.738*
*Significantly greater than controls, P < 0.005.
aration which would result in an increase in marrow
star volume are also clearly evident in the microradio1.8**** graphs (Fig. 2).
8.7 2
30.6 f 3.4
31.2 t 6.3****
3.8 t 0.8****
26.3 t 8.3**
*
TABLE 2. Marrow star volumes determined by image
analysis of microradiographs of cross- and
longitudinal-sections of the lumbar vertebral bodies
from aged control and OVX rats
170 t 17*
252 2 61****
312 t 31***
253 t 52
167 t 17
*Significantly different from controls, P < 0.05.
**Significantly different from controls, P < 0.025.
***Significantly different from controls, P < 0.01.
****Significantly different from controls, P < 0.005.
Miller et al., 1991; Kalu, 1991). This decrease in cancellous bone was particularly evident in the central
lumbar vertebral body (Fig. 2a-d) and the central
metaphysis of the humerus (Fig. 2e,f). Cancellous bone
was not observed below the metaphyseal primary spongiosa in the center of the proximal humerus in any of
the OVX animals (Fig. Zf), whereas it was consistently
found in all of the intact, control animals (Fig. Be).
Scanning Electron Microscopy
There was a dramatic difference in the structure and
amount of metaphyseal spongiosa in the humerii of the
OVX animals (Fig. 3) when compared with controls
(Fig. 4). The marked reduction in cancellous bone observed in the OVX animals compared with controls correspond to the microradiographic images (Figs. 2e,f).
The metaphyseal cancellous bone in the control animals consisted of plates and rods in a honeycomb-type
pattern. While the lateral metaphyseal trabeculae
were oriented preferentially along the longitudinal
axis of the bone, the central metaphyseal trabeculae
were less ordered. In these aging control animals, the
plate-type trabeculae were most evident in the lateral
portions of the metaphysis (Figs. 4 , 5 ) while in the central metaphysis the spicules were thin with fewer connections (Fig. 6) than in the more lateral portions (Fig.
5).
There was no cancellous bone in the central metaphyseal region below the primary spongiosa in the
OVX animals (Figs. Zf, 3). The primary spongiosa in
these old animals formed a very thin mineralized plate
adjacent to the growth plate (Fig. 7). In the lateral
metaphyseal region in the OVX animals, the bone spImage Analyses
icules were usually shaped as long struts spanning
Image analyses were done on digitized, Z-dimen- from beneath the epiphyseal growth plate, at the prisional images taken from the microradiographs of the mary spongiosa, t o the metaphyseal cortex (Figs. 3, 7sagittal and cross-sections of the lumbar vertebral bod- 10). These bone spicules were generally quite straight,
ies. There were substantial differences in the types of had a fairly uniform diameter and ran along the lonstruts (defined in Fig. 1)and their relative sizes in the gitudinal axis of the bone. The longitudinal trabecular
OVX rats compared with the age-matched, controls struts were often interconnected by rod-like transverse
(Table 1).In both the cross and sagittal sections of the struts (Fig. 9) which were usually much smaller in divertebral bodies, there were significant increases in ameter than the connecting longitudinal trabeculae.
the relative percentages of free-free, cortex-free, and The longitudinal trabeculae had a broad base a t the
cortex-node trabecular struts, with a significant de- insertion into the mineralized tissue adjacent to the
crease in the percentage of node-node-type struts. growth plate (Fig. 10).
There were also significant increases in the average
DISCUSSION
lengths of the free-free, node-free, and node-node trabecular struts.
There were profound differences in cancellous bone
The bone marrow star volume analyses were also volume and structure in the animals that had been
performed from the images taken from the sagittal and OVX for 1.5 years compared with the sham-OVX anicross-sections of the lumbar vertebral bodies (Table 2). mals. A decrease in cancellous bone mass with the loss
The marrow star volumes were substantially increased of ovarian function was expected as this is one of the
in the OVX rats compared with controls when mea- defining features of the OVX rat model (Saville, 1969;
sured in both planes. The increases in trabecular sep- Wronski et al., 1985; Kalu, 1991). There were, how-
438
S.C. MILLER AND T.J. WRONSKI
Fig. 5. Lateral cancellous bone in the proximal humerus from a control animal. The cancellous bone is
structured as a broad trabeculae plates (P)and rods (R). X45.
Fig. 6. In the central metaphyseal regions of the control animals there are fewer plates, as observed
primarily in the lateral regions (Fig. 5), and more bone spicules. Many of the spicules in the aging
animals are very thin (arrowheads)and often are not well connected with other spicules. x 60.
ever, dramatic differences in cancellous bone structure
between the OVX and sham-operated controls. Structural analyses of two-dimensional sagittal and crosssectional plane images of the lumbar vertebral cancellous bone demonstrate less bone connectivity in the
OVX animals compared with the controls. There were
relative increases in the free-free and cortex-free type
trabecular struts, but a decrease in the node-node type
struts. The lengths of the free-free, node-free and nodenode type struts were greater in the OVX animals compared with controls. These increases in trabecular strut
length could be attributed to a decrease in connectivity,
and thus nodes, between the struts. Decreases in trabecular connectivity have also been reported in cancellous bone from aging humans using both morphological
(Arnold et al., 1966; Arnold, 1980) and morphometric
approaches (Compston et al., 1987; 1989).
The star volume analyses of the cancellous bone of
the lumbar vertebral bodies also indicated substantial
differences in cancellous bone architecture in the OVX
animals compared with controls. Bone marrow star volumes were increased in images obtained from cross and
sagittal sections. This indicates a greater trabecular
separation in the OVX animals compared with controls. Yoshida et al. (1991) reported that after 9 months
following OVX in rats there was substantially de-
creased trabecular number, but not trabecular thickness in cancellous bone areas. This was particularly
evident in central spongiosa areas of the bone, similar
to that observed in this study, This loss of individual
trabeculae results in a larger marrow star volume, reported here. The loss of individual structural elements
by removal of individual trabeculae and perhaps perforation of others, can result in less continuity and connectivity between the remaining structural elements,
as indicated in this study from the nodal analyses. An
increase in marrow star volume due to the removal and
perforation of individual bone trabeculae occurs in aging human cancellous bone (Vesterby et al., 1989).
The differences in the 3-dimensional architecture of
metaphyseal cancellous bone in the OVX compared
with control rats was evident from the scanning electron micrographs of the proximal humerii. There was
virtually no cancellous bone in the central metaphyseal region in the OVX animals, consistent with the
reported loss of central metaphyseal bone following
OVX in other long bones including the femur (Miller et
al., 1991) and tibia (Wronski et al., 1985; Yoshida et al.,
1991). The remaining metaphyseal cancellous bone
was found in the lateral metaphysis spanning from the
mineralized tissue adjacent to the epiphyseal growth
plate (the remnant of the primary spongiosa) to the
CANCELLOUS BONE I N OVARIECTOMIZED RATS
439
Fig.7. The bone spicules remaining in the lateral metaphysis of the
proximal humerii from the OVX animals consist primarily of long and
relatively straight longitudinal struts. These longitudinal struts usually span from the mineralized tissues adjacent to the growth plate
(GP)to the metaphyseal cortex (0.
x 35.
Fig. 8 . Detail of the cylindrical longitudinal struts extending from
the mineralized primary spongiosa to the cortex in the humeral metaphysis from an OVX animal. No cancellous bone was found in the
central metaphyseal regions (*). x 55.
metaphyseal cortex. In the control animals much of the
cancellous bone consisted of plates and rods whereas in
the OVX animals most of the bone consisted of fairly
straight rods. The remodeling of the trabecular plates
into rods in the OVX animals and no doubt to some
extent in the aging controls, is consistent with pattern
of cancellous bone loss in the aging and osteoporotic
human where plate-type trabeculae are initially converted to rod-type trabeculae by perforation of the trabecular plates (Arnold, 1970; Singh, 1977; Parfitt et
al., 1983).
Skeletal tissues are adaptable to changes in usage
and mechanical loading (Rubin, 1984; Lanyon et al.,
1986). For example, in humans and experimental animals an increase in mechanical usage and loading increases bone modeling and remodeling to increase bone
mass. While there were substantial changes in the volume and structure of cancellous bone in the OVX rat,
the bone probably remains responsive to mechanical
stimuli. Endurance training attenuates bone loss in
rats following OVX (Donahue et al., 1988) while skeletal underloading accentuates bone loss (Okumura et
al., 1988; Bagi et al., 1992). Yoshida et al. (1991) suggested that trabecular loss following OVX occurs in
regions where the mechanical stresses are lowest. The
loss of trabeculae in the central regions of the cancellous bone following OVX reflects these differences in
biomechanical properties. The results from the present
study support this hypothesis. The longitudinal orientation of the rods in the OVX animals is consistent
with the propagation of skeletal loading forces through
the longitudinal axis of the bone from the articular
surfaces, through the epiphysis and epiphyseal plate to
the metaphyseal and diaphyseal cortex. The thinner
transverse rods that connected the larger longitudinal
trabeculae were often much thinner than the rods they
connected. As much of the normal loading force in bone
is along the longitudinal axis, the thinner transverse
rods may serve primarily as stabilizers for the weightand force-bearing longitudinal rods. This is consistent
with the appearance of rod-like bone spicules that connect trabecular plates and thicker vertical columns in
models of aging human bone (Jensen et al., 1990).
The loss of ovarian function following ovariectomy
removes or reduces the endocrine signals that maintain skeletal mass for reproductive purposes. In rodents there are changes in the maternal skeletal metabolism during pregnancy providing a calcium
reservoir for fetal skeletal mineralization and during
lactation for milk production (Miller et al., 1986).During the first reproductive cycle in rats, there is a substantial loss of central metaphyseal cancellous bone
(Miller et al., 1986), quite similar to the bone loss observed following OVX. These observations provide further evidence that the central metaphyseal bone found
in virgin female rats is more metabolically active and
S.C. MILLER AND T.J. WRONSKI
440
Fig. 9. The longitudinal struts in the metaphyses of the OVX animals are often interconnected with
smaller, cylindrical transverse struts (arrows). x 55.
Fig. 10. Detail of the insertion of a longitudinal strut into the mineralized tissue of the primary
spongiosa adjacent to the growth plate. The base of the longitudinal strut is spread over the mineralized
piate(*). x loo.
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structure, terms, change, osteopenia, long, cancellous, rats, bones, ovariectomized
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