Comparative Medicine Vol 61, No 1

Copyright 2011 February 2011

by the American Association for Laboratory Animal Science Pages 76–85

Comparative Bone Anatomy of

Commonly Used Laboratory Animals:
Implications for Drug Discovery

Cedo M Bagi,* Edwin Berryman, and Maria R Moalli

To accommodate functional demands, the composition and organization of the skeleton differ among species. Microcomputed
tomography has improved our ability markedly to assess structural parameters of cortical and cancellous bone. The current study
describes differences in cortical and cancellous bone structure, bone mineral density, and morphology (geometry) at the proximal
femur, proximal femoral diaphysis, lumbar vertebrae, and mandible in mice, rats, rabbits, dogs, and nonhuman primates. This work
enhances our understanding of bone gross and microanatomy across lab animal species and likely will enable scientists to select
the most appropriate species and relevant bone sites for research involving skeleton. We evaluated the gross and microanatomy of
the femora head and neck, lumbar spine, and mandible and parameters of cancellous bone, including trabecular number, thickness,
plate separation, and connectivity among species. The skeletal characteristics of rabbits, including a very short femoral neck and
small amounts of cancellous bone at the femoral neck, vertebral body, and mandible, seem to make this species the least desirable
for preclinical research of human bone physiology; in comparison, nonhuman primates seem the most applicable for extrapola-
tion of data to humans. However, rodent (particularly rat) models are extremely useful for conducting basic research involving
the skeleton and represent reliable and affordable alternatives to dogs and nonhuman primates. Radiology and microcomputed
tomography allow for reliable evaluation of bone morphology, microarchitecture, and bone mineral density in preclinical and
clinical environments.

Abbreviation: mCT, microcomputed tomography.

The skeleton is a mechanically optimized biological system
and its composition and organization accommodate to the func-
tional demands placed on it. In general, the mechanical properties
of bone are determined by bone geometry, mineral density, and
structure.6,9,16,64,69 Hydroxyl apatite provides most of the strength
and stiffness to the skeleton and permits the use of radiologic
technologies to assess bone mass and structure. New technologies
including dual-energy X-ray absorbtiometry, quantitative com-
puted tomography, and microcomputed tomography (mCT) have
been developed to assess the gross and microanatomy of the skel-
eton during health and disease. Using noninvasive methodology
to describe bone anatomy and structure has broad application in
several scientific disciplines, including medical and pharmaceuti-
cal research, animal health and meat industry, and biologic and
forensic anthropology.22,46,52 The current study focuses on using
radiography and mCT to describe major skeletal differences be-
tween several commonly used laboratory animal species. These
differences manifest in the physical characteristics of their skele-
tons, including their morphology and dimensions, but differences
in growth rates and laboratory conditions might also influence
cortical and cancellous bone structures as well as the biochemical
composition of bone.1,3,43 Using Wessler’s definition70 of an animal
model, Kalu37 has suggested that the convenience, relevance, and
Received: 22 Jun 2010. Revision requested: 09 Aug 2010. Accepted: 03 Oct 2010.
Global Science & Technology, WWCM, Pfizer, Groton, Connecticut.
*
Corresponding author. Email: cedo.bagi@pfizer.com
appropriateness (compatibility to humans) of particular animal
models should be considered when deciding what laboratory
animals to use to study the skeletal effects of novel therapeutics
aimed to prevent or cure osteoporosis. Kalu’s suggestions36 likely
can be applied to all areas of pharmaceutical research involving
animals. Regardless of the animal model or species is used to
study intended or undesired skeletal effects of novel compounds,
the decreased physical activity of animals under laboratory con-
ditions and differences in skeletal mechanical properties between
humans (bipeds) and lab animals (quadrupeds) should always
be taken into account.12,18,49,51,55,61 Along these lines, the Food and
Drug Administration requires that novel therapies in osteoporosis
research must be tested both in rodents (preferably rats) as well as
a large animal model.61 This requirement is based on the fact that
growth plates in rodents remain open throughout their life span,
allowing bone growth and modeling to continue, resembling
immature skeleton.28,71 However, the reason for using a second
species in preclinical skeletal research is the lack of the Haver-
sian system in rodents; therefore, other species, including dogs,
nonhuman primates, pigs, and sheep should be considered.36,49,55
Because the skeletal system is highly responsive to mechanical
loads that influence bone geometry and structure as well as the
rate of bone remodeling, the structural properties of cancellous
and cortical bone at several skeletal sites with different mechani-
cal properties, such as the femoral neck, vertebrae, and mandible,
should be assessed.5,9,10,17,53,63,67

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Table 1. mCT parameters used to collect and analyze cortical and cancellous bone structure and bone mineral density
Mouse Rat Rabbit Canine Cynomolgus macaque
Mid-diaphysis
No. of slices 20 20 20 20 20
Thickness (mm) 0.21 0.25 0.30 0.38 0.38
Resolution (µm) 10.5 12.5 15.0 19.0 19.0

Femoral head
No. of slices 25 50 25 50 50
Thickness (mm) 0.03 0.65 0.30 0.95 0.95
Resolution (µm) 10.5 12.5 15.0 19.0 19.0

Femoral neck
No. of slices 25 50 25 50 50
Thickness (mm) 0.03 0.65 0.30 0.95 0.95
Resolution (µm) 10.5 12.5 15.0 19.0 19.0

By using radiology and mCT to describe major skeletal dif- 1 male cynomolgus macaque (age, 5 y). Therefore, all animals
ferences among common laboratory animals, we hope to help from which bones were collected had reached sexual maturity
investigators to pick the right species when conducting animal before they were used in the original studies, and radiography
studies aiming to address issues associated with skeletal health. confirmed sealed growth plates in macaques, dogs, and rabbits.
In the present study, we compared bone properties at 3 skeletal X-ray and mCT measurements. Femurs. The femurs used for
sites with different mechanical properties—the proximal femur, mCT analysis in this study were collected from animals that were
lumbar vertebrae, and mandible—in laboratory mice, rats, rab- euthanized according to their respective study protocols. Whole
bits, dogs, and cynomolgus macaques. femurs were harvested at necropsy, cleaned of soft tissue, and
fixed in 10% formalin. Proximal femurs were radiographed by us-
ing a digital X-ray system (Faxitron X-ray, Wheeling, IL) with the
Materials and Methods following manufacturer-recommended settings according to the
Bone samples. Experimentation using laboratory animals in-
size of the bone samples: mouse: 10 s at 25 kV; rat: 12 s at 30 kV;
cluding mice (Mus musculus, C57BL6), rats (Rattus norvegicus,
rabbit: 12 s at 35 kV; dog: 12 s at 35 kV and macaques: 12 s at 35
CD/SD), rabbits (Oryctolagus cuniculus, New Zealand white),
kV. Radiographic images were used to assess the gross anatomy
dogs (Canis familiaris, beagle), and nonhuman primates (Macaca
of the region of interest for every animal used in this study. Be-
fascicularis, Mauritian cynomolgus macaque) is a mandatory step
cause large differences in size and morphology of the skeletal
regulated by the Food and Drug Administration for each Inves-
areas between species prevented use of the same region of interest
tigational New Drug Application that is aimed to minimize po-
across species, we first ran ‘scout’ mCT images for each anatomic
tential harm of novel drug candidates to patients that participate
site and for each species to ensure that we could consistently and
in the clinical trials. The safety preclinical studies in laboratory
reproducibly scan and analyze particular target regions in each
species require only small samples of bone tissue from that used
species and that size of the target picked permitted meaningful
for pathologic examination; the vast majority of the skeleton fre-
analysis of cancellous bone structure. At the same time, the op-
quently is discarded without use in further research. To evaluate
timal thickness and resolution parameters were determined for
the bone morphology and structure of cancellous and cortical
each species and each anatomic location that conformed to the
bone at the proximal femur, lumbar vertebrae, and mandible, we
limits of the imaging system and study goals.20 This optimiza-
collected the bones from euthanized animals that were used in
tion ensured that trabecular thickness and number could be cap-
various preclinical studies. We used only animals that received
tured, measured, and analyzed when the number and thickness
vehicle only in these previous studies to minimize the chance
of slices chosen to capture bone structure at the target region in
of drug-associated changes in bone structure and bone mineral
each species assessed in this study were applied. Results from
density. All animals in the original studies were maintained in
the pilot studies then were applied to capture the exact cortical or
an AAALAC-accredited research facility, and the original animal
cancellous bone areas that we attempted to measure by using the
procedures were IACUC-approved and conformed to the Guide
optimal mCT settings.20
for the Care and Use of Laboratory Animals.26 The right femurs, lum-
Femurs were analyzed by using the VivaCT 40 mCT system
bar vertebrae (L4, L5), and mandibles were collected immediately
(Scanco Medical, Bassersdorf, Switzerland) with the following
after necropsy, cleaned of soft tissues, and placed in 10% formalin
settings: mouse, 45 kVp at 88 µA at high resolution (10 µm); rat,
for 24 h, transferred to 70% alcohol, and stored at 4 °C before be-
55 kVp at 109 µA at high resolution (12.5 µm); rabbit, 55 kVp at
ing used for X-ray and mCT analyses. The numbers of animals
109 µA at high resolution (15 µm); dog, 70 kVp at 85 µA at high
used in the current study were 6 male and 6 female mice (age,
resolution (19 µm); and NHP, 70 kVp at 85 µA at high resolution
5 mo); 6 male and 6 female rats (age, 5 mo); 4 male and 4 female
(19 µm). Cancellous bone parameters at the femoral neck and
rabbits (age, 16 mo old); 4 male and 3 female dogs (age, 3.5 to 4
head were analyzed; these parameters included tissue volume
y old); 2 male and 3 female cynomolgus macaques (age, 4 y) and
(bone and bone marrow combined), bone volume, bone volume:
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Figure 1. Radiographic images of the femoral proximal diaphysis captured by digital radiography from human, nonhuman primate, dog, rabbit, rat,
and mouse. The human sample was used for reference only. The angle between the femoral shaft and the femoral neck is shown in green. Dotted blue
lines and associated numbers indicate the sites at the proximal femur where structural parameters were measured by mCT: 1, femoral head; 2, femoral
neck; and 3, proximal femoral diaphysis.

tissue volume ratio, trabecular number, trabecular thickness,
trabecular separation (distance between individual trabeculae),
trabecular connectivity (the number of times per unit area that
adjacent trabeculae touch each other) and bone mineral density
(g Ca2+/cm2). Cortical bone parameters were analyzed at femoral
proximal diaphysis and included tissue volume, bone volume,
bone volume:tissue volume ratio, marrow volume, and cortical
thickness. A single sample of human proximal femur was ob-
tained through a tissue bank and was used only as a standard for
comparison. Because of large differences in the size and shape of
the proximal femur among species, the setup presented in Table 1
was applied to analyze cancellous and cortical bone parameters
by using mCT.
Lumbar vertebrae. L4 and L5 were collected at necropsy and care-
fully cleaned of soft tissue; 3 to 5 d later, only L4 vertebra from each
animal enrolled in the study was radiographed by using a digital
X-ray system (Faxitron X-Ray LLC, Wheeling, IL) at the same set-
tings described earlier for femurs. Only cancellous bone parame-
ters were analyzed at vertebral bodies and included tissue volume,
bone volume, tissue volume: bone volume ratio, trabecular num-
ber, trabecular thickness, trabecular separation, trabecular connec-
tivity, and bone mineral density. Due to their very thin vertebral
bodies which contains very little to no cancellous bone, the region
of interest for rabbit lumbar vertebrae differed from that of other
species and was placed at the bottom of the lumbar vertebral body,
which provides sufficient cancellous bone for mCT measurements.

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Table 2. Cancellous and cortical bone parameters obtained from cynomolgus macaques by using mCT
Femoral head Femoral neck Proximal diaphysis Lumbar vertebrae Mandible
Tissue volume (mm )3
124.67 ± 33.22 59.25 ± 21.84 355.9 ± 83.4 72.42 ± 34.3 8.95 ± 0.31
Bone volume (mm3) 43.96 ± 5.03 17.93 ± 4.25 176.0 ± 37.7 8.13 ± 1.43 5.30 ± 1.20
Bone volume:tissue volume (ratio) 0.36 ± 0.05 0.32 ± 0.08 0.50 ± 0.03 0.12 ± 0.03 0.59 ± 0.14
No. of trabeculae (per mm) 2.70 ± 0.27 2.04 ± 0.23 not done 1.89 ± 0.39 2.36 ± 0.39
Trabecular thickness (μm) 0.14 ± 0.02 0.15 ± 0.02 not done 0.06 ± 0.004 0.25 ± 0.05
Trabecular separation (μm) 0.24 ± 0.04 0.34 ± 0.08 not done 0.49 ± 0.1 0.18 ± 0.09
Trabecular connectivity (per mm3) 63.44 ± 19.05 23.4 ± 6.8 not done 80.6 ± 34.3 31.69 ± 13.16
Bone mineral density (g/cm2) 816.8 ± 14.8 823.6 ± 17.4 19.5 ± 2.8 814.2 ± 19.8 844.3 ± 29.3
Cortical thickness (mm) not done not done 1041.0 ± 17.8 not done not done
Marrow volume (mm3) not done not done 179.9 ± 47.7 not done not done

Table 3. Cancellous and cortical bone parameters obtained from dogs by using mCT
Femoral head Femoral neck Proximal diaphysis Lumbar vertebrae Mandible
Tissue volume (mm )3
160.14 ± 12.23 39.68 ± 2.20 422.4 ± 54.0 72.65 ± 22.9 8.83 ± 0.34
Bone volume (mm3) 59.72 ± 10.87 8.83 ± 1.50 201.1 ± 17.0 9.65 ± 1.95 3.13 ± 1.16
Bone volume:tissue volume (ratio) 0.37 ± 0.05 0.22 ± 0.04 0.48 ± 0.02 0.14 ± 0.02 0.35 ± 0.12
No. of trabeculae (per mm) 3.58 ± 0.14 2.44 ± 0.21 not done 2.54 ± 0.08 1.93 ± 0.27
Trabecular thickness (μm) 0.10 ± 0.02 0.09 ± 0.01 not done 0.05 ± 0.01 0.18 ± 0.05
Trabecular separation (μm) 0.18 ± 0.01 0.32 ± 0.04 not done 0.34 ± 0.003 0.35 ± 0.10
Trabecular connectivity (per mm3) 92.30 ± 14.42 52.2 ± 11.2 not done 112.7 ± 20.0 31.94 ± 7.71
Bone mineral density (g/cm2) 850.3 ± 7.0 871.2 ± 9.5 1058.5 ± 13.3 855.9 ± 12.8 904.39 ± 14.2
Cortical thickness (mm) not done not done 14.3 ± 2.7 not done not done
Marrow volume (mm3) not done not done 221.3 ± 37.0 not done not done

Table 4. Cancellous and cortical bone parameters obtained from rabbits by using mCT
Femoral head Femoral neck Proximal diaphysis Lumbar vertebrae Mandible
Tissue volume (mm )3
5.60 ± 1.19 11.79 ± 1.56 156.8 ± 9.8 6.96 ± 0.46 1.00 ± 0.03
Bone volume (mm3) 3.22 ± 0.58 3.44 ± 1.02 59.7 ± 2.9 0.67 ± 0.26 0.46 ± 0.17
Bone volume:tissue volume (ratio) 0.58 ± 0.04 0.29 ± 0.07 0.38 ± 0.02 0.24 ± 0.04 0.46 ± 0.17
No. of trabeculae (per mm) 3.83 ± 0.65 2.28 ± 0.35 not done 2.68 ± 0.21 2.15 ± 0.53
Trabecular thickness (μm) 0.15 ± 0.02 0.15 ± 0.02 not done 0.09 ± 0.01 0.21 ± 0.04
Trabecular separation (μm) 0.11 ± 0.02 0.32 ± 0.07 not done 0.29 ± 0.03 0.30 ± 0.22
Trabecular connectivity (per mm3) 138.2 ± 48.1 39.2 ± 10.3 not done 68.9 ± 22.2 6.74 ± 5.48
Bone mineral density (g/cm2) 718.9 ± 27.1 785.1 ± 12.5 1167.5 ± 17.5 718.9 ± 10.4 973.6 ± 44.7
Cortical thickness (mm) not done not done 9.5 ± 0.4 not done not done
Marrow volume (mm3) not done not done 97.2 ± 8.6 not done not done

Mandibles. The right mandibles were collected at necropsy and of both genders in each species analyzed. The results obtained
carefully cleaned of soft tissue; 3 to 5 d later the mandibles were from all subjects of a particular species were used (regardless of
radiographed by using a digital X-ray system (Faxitron X-Ray, sex) to generate summary data, reported as mean ± 1 SD.
Wheeling, IL) at the same settings described earlier for femurs.
Cancellous bone parameters were analyzed at mandibular bod-
Results
ies and included only the area below the first and second molars.
Femur. The gross anatomy of the human proximal femur has
Connective tissue surrounding roots of the first and second mo-
distinct dissimilarity from the laboratory species. The most obvi-
lars and cortical bone shell were not included in the analyses. The
ous distinctions included the angle between the diaphyseal shaft
following parameters were evaluated by mCT: tissue volume,
and femoral neck, the length and width of the femoral neck, and
bone volume, bone volume: tissue volume ratio, trabecular num-
size and shape of the femoral head (Figure 1).
ber, trabecular thickness, trabecular separation, trabecular con-
Femoral head. Results from mCT analyses of the cancellous
nectivity, and bone mineral density.
bone at the femoral head provide values for cancellous bone
Statistical analysis Statistical analyses of interspecies differences
volume (in mm3) in cynomolgus macaques (43.96 ± 5.03), dogs
were not carried out due to large variations in size and shape of
(59.72 ± 10.87), rabbits (3.22 ± 0.58), rats (2.59 ± 0.90) and mice
the bones between species, relatively small sample size, and use

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Table 5. Cancellous and cortical bone parameters obtained from rats by using mCT
Femoral head Femoral neck Proximal diaphysis Lumbar vertebrae Mandible
Tissue volume (mm )3
3.51 ± 1.17 1.49 ± 0.20 2.66 ± 0.12 3.35 ± 0.20 0.97 ± 0.06
Bone volume (mm3) 2.59 ± 0.90 0.99 ± 0.15 1.01 ± 0.03 1.10 ± 0.11 0.60 ± 0.14
Bone volume:tissue volume (ratio) 0.74 ± 0.06 0. 66 ± 0.07 0.38 ± 0.02 0. 33 ± 0.03 0. 61 ± 0.15
No. of trabeculae (per mm) 5.58 ± 0.54 5.32 ± 0.18 not done 4.77 ± 0.31 3.33 ± 0.29
Trabecular thickness (μm) 0.13 ± 0.02 0.13 ± 0.02 not done 0.07 ± 0.003 0.19 ± 0.06
Trabecular separation (μm) 0.05 ± 0.01 0.06 ± 0.01 not done 0.14 ± 0.01 0.11 ± 0.04
Trabecular connectivity (per mm3) 227.6 ± 39.1 171.7 ± 33.7 not done 178.6 ± 29.2 23.65 ± 8.33
Bone mineral density (g/cm2) 788.1 ± 11.6 928.1 ± 15.9 1117.6 ± 9.5 760.4 ± 8.0 1024.3 ± 42.5
Cortical thickness (mm) not done not done 0.44 ± 0.03 not done not done
Marrow volume (mm3) not done not done 1.64 ± 0.12 not done not done

Table 6. Cortical and cancellous bone parameters obtained from mice by using mCT
Femoral head Femoral neck Proximal diaphysis Lumbar vertebrae Mandible
Tissue volume (mm3) 0.25 ± 0.06 0.08 ± 0.02 0.56 ± 0.07 0.77 ± 0.15 0.11 ± 0.00
Bone volume (mm3) 0.19 ± 0.06 0.05 ± 0.01 0.22 ± 0.04 0.17 ± 0.03 0.08 ± 0.01
Bone volume:tissue volume (ratio) 0.77 ± 0.12 0.62 ± 0.05 0.38 ± 0.03 0.22 ± 0.03 0.69 ± 0.11
No. of trabeculae (per mm) 6.16 ± 1.55 8.53 ± 0.76 not done 5.98 ± 0.49 5.44 ± 0.47
Trabecular thickness (μm) 0.13 ± 0.05 0.13 ± 0.05 not done 0.04 ± 0.003 0.13 ± 0.02
Trabecular separation (μm) 0.04 ± 0.01 0.04 ± 0.003 not done 0.13 ± 0.02 0.06 ± 0.02
Trabecular connectivity (per mm3) 247.5 ± 127.5 482.5 ± 127.5 not done 541.5 ± 91.0 62.76 ± 33.36
Bone mineral density (g/cm2) 898.5 ± 85.4 973.7 ± 36.9 1206.4 ± 24.5 845.3 ± 10.7 1286.9 ± 62.6
Cortical thickness (mm) not done not done 0.23 ± 0.03 not done not done
Marrow volume (mm3) not done not done 0.35 ± 0.3 not done not done

Figure 2. 2D (black) and 3D (blue) images of the femoral head obtained by mCT.

(0.19 ± 0.06; Tables 2 to 6, Figures 2 to 6). The ratio of bone volume
to tissue volume ranged from 0.77 ± 0.12 and 0.74 ± 0.06 in mice
and rats, as compared with 0.58 ± 0.04 in rabbits, 0.37 ± 0.05 in
dogs, and 0.36 ± 0.05 in cynomolgus macaques. Trabecular num-
ber (per mm) was 2.70 ± 0.27 in cynomolgus macaques, 3.58 ± 0.14
in dogs, 3.83 ± 0.65 in rabbits, 5.58 ± 0.54 in rats, and 6.16 ± 1.55
in mice. Trabecular thickness was fairly consistent among spe-
cies and ranged from 0.10 μm in dogs to 0.15 μm in rabbits. As a
result, trabecular connectivity was high in mice, followed by rats
and rabbits, dogs, and cynomolgus macaques. Mineral density of
cancellous bone at the femoral head was similar among all species
involved in this study.
Femoral neck. The morphology of the femoral neck and adjoin-
ing area, including the greater trochanter and intertrochanteric
region, showed a great deal of variability among the lab animal
species evaluated (Figure 3). The tissue volume parameter in
the femoral neck varied between compared species. The cancel-
lous bone volume (in mm3) at the femoral neck was 17.93 ± 4.25
in cynomolgus macaques, 8.83 ± 1.50 in dogs, 3.44 ± 1.02 in rab-
bits, 0.99 ± 0.15 in rats, and 0.50 ± 0.01 in mice (Tables 2 to 6).

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Figure 3. 2D (black) and 3D (blue) mCT images of the femoral neck with cancellous and cortical bone and intertrochanteric region in dog. The intertro-
chanteric region in dog was captured because the gross anatomy of the proximal femur and limitations of the mCT holder did not allow for capturing
only the femoral neck region.

Figure 4. 2D (black) and 3D (blue) images of the proximal femoral diaphysis obtained by mCT.

Trabecular number at the femoral neck was 0.32 ± 0.08 in cyno-
molgus macaques, 0.22 ± 0.04 in dogs, 0.29 ± 0.07 in rabbits, 0.66
± 0.07 in rats, and 0.62 ± 0.05 in mice. Trabecular thickness was
fairly consistent among all species, ranging from 0.09 to 0.15 μm.
The mineral density of cancellous bone at the femoral neck was
also fairly consistent among all laboratory species involved in this
study (Table 3).
Proximal diaphysis. The ratio of cortical bone volume to tissue
volume was 0.50 ± 0.03 in cynomolgus macaques, 0.48 ± 0.04 in
dogs, 0.38 ± 0.02 in rabbits, 0.38 ± 0.02 in rats, and 0.38 ± 0.03 in
mice. The cortical bone thickness (in mm) was 19.5 ± 2.8 in cyno-
molgus macaques, 14.3 ± 2.7 in dogs, 9.5 ± 0.4 in rabbits, 0.44 ±
0.03 in rats, and 0.23 ± 0.03 in mice. Cortical bone mineral density
(g/cm2) was 1041.0 ± 17.8 in cynomolgus macaques, 1058.5 ± 13.3
in dogs, 1167.5 ± 17.5 in rabbits, 1117.6 ± 9.5 in rats, and 1206.4 ±
24.5 in mice. (Tables 2 to 6, Figures 2 to 6).
Lumbar vertebrae. Radiographs and mCT images revealed
large differences in bone morphology and microanatomic struc-
ture of the cancellous bone of lumbar vertebrae (Figures 2 to 6).
The ratio between bone volume and tissue volume ranged from
0.22 ± 0.03 to 0.33 ± 0.03 in mice and rats, as compared with 0.24 ±
0.04 in rabbits, 0.14 ± 0.02 in dogs, and 0.12 ± 0.03 in cynomolgus
macaques. Trabecular number (per mm) at the lumbar vertebral
bodies was 1.89 ± 0.39 in cynomolgus macaques, 2.54 ± 0.08 in
dogs, 2.68 ± 0.21 in rabbits, 4.77 ± 0.31 in rats, and 5.98 ± 0.49 in
mice. Trabecular thickness (in mm) at the lumbar vertebral was
0.060 ± 0.004 in cynomolgus macaques, 0.05 ± 0.01 in dogs, 0.09
± 0.01 in rabbits, 0.070 ± 0.003 in rats, and 0.040 ± 0.003 in mice
(Tables 2 to 6). Relative to other species, rabbits exhibited a very
narrow mid-portion of the vertebral body (Figures 5).
Mandible. The morphology of the mandible was very different
among the lab animal species studied (Figure 6). Mice and rats
have very similar mandibular bones: the incisors extend through-
out the entire mandible. Incisor teeth in rabbits are much shorter
and extend only through the rostral third of the mandible. The
morphologic features of the premolar and molar teeth of rabbits
are also very different from those of all other evaluated species.
Because of differences in root morphology, obtaining precise mea-
surements in the identical area of trabecular bone at the site of
the second molar was difficult. The assembly of the trabecular

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Figure 5. 2D (black) and 3D (blue) images of lumbar vertebrae obtained by mCT. The green box in the 2D images indicates the region of interest where
concellous bone structural analyses was performed. Note that the target region in rabbit lumbar spine is different from that of other species because
of the very thin vertebral body in rabbits, which contains very little to no cancellous bone. Therefore, the region of interest for rabbit lumbar vertebrae
was placed at the bottom of the lumbar vertebral body to obtain sufficient cancellous bone for mCT measurements.

network and cortico-cancellous morphology was qualitatively The size and gross anatomy of the proximal femur varied sub-
different among species due to presence of the long incisors un- stantially among the laboratory species considered in this study.
derneath the molars in mice and rats, as well as the depth, num- The features with most obvious variation include the size of the
ber, and position of the molar roots (Tables 2 to 6, Figures 6). femoral head, length and angle of the femoral neck, size and mor-
phology of the greater trochanter, and shape and size of the inter-
trochanteric area. Variation among species in the 3D orientation
Discussion of the femoral neck relative to the diaphysis created difficulties in
The majority of skeletal research in laboratory animals is fo-
consistently positioning bone specimens and accurately scanning
cused on metabolic bone diseases because osteoporoses of vari-
the regions of interest. Consequently, the cross-sectional area (20
ous etiologies are recognized as some of the most important
to 50 slices per anatomic site) of cancellous bone chosen for mCT
public problems today.35 The entire region of the proximal femur,
evaluation was not identical among individual measurements
including the intertrochanteric area, femoral neck, and femoral
in the same species or among the different species used in our
head, is of enormous importance for human pathophysiology
analysis. The results obtained by mCT revealed that trabecular
because hip fractures result in considerable morbidity and mor-
bone volume, number, and separation measured at the femoral
tality with massive socio-economic consequences.39 In addition
head and neck vary greatly among laboratory animals. Similar
to that in the proximal femur, bone loss in the spine and jaws is
to the proximal femur of humans, the femoral head and neck ar-
associated with osteoporosis and aging.23,37,41,42 For example, there
eas of the proximal femur from dogs and cynomolgus macaques
is a strong correlation between mandibular bone mass and the
contain a considerable quantity of cancellous bone.2,30,40,73 Results
decline in bone mass at other skeletal sites.3,20,29 Therefore, the pri-
from the present study indicate that the trabecular network in the
mary focus of our study was to compare anatomic and structural
proximal femur has fairly constant thickness across all species,
bone features in the proximal femur, lumbar vertebrae, and man-
leading us to conclude that trabecular separation and connec-
dible among different laboratory animals because these anatomic
tivity contributes to variation in trabecular number among spe-
sites are involved in the pathophysiology of human osteoporoses
cies. Results in dogs and cynomolgus macaques from this study
and are used most frequently in preclinical research involving the
support earlier findings that at proximal femur where cancellous
skeleton. In addition to their obvious value for studies involving
bone predominates, the combination of volumetric bone mineral
osteoporoses, the imaging techniques used in this study have
density should be measured in concert with trabecular structural
the potential to be applied to any research involving skeleton.
parameters, particularly trabecular thickness and number, be-
Because bone strength is difficult to assess in clinic, radiologic
cause these 2 parameters used in combination better predict bio-
methods typically are used to assess 2 primary determinants of
mechanical properties of the proximal femur rather than does any
bone strength: mineralization and structure.45 Even though re-
single parameter alone.34,57 Despite subtle variation in the mineral
searchers agree that bone mineral density is the single most im-
density of the cancellous and cortical bone at femoral neck and
portant predictor of bone health and strength, recent studies have
head, density values were similar among species. The somewhat
shown that this measure alone may be insufficient to determine
higher values in mice and rats could be due to fewer, but thicker,
the strength of cancellous bone and that trabecular architecture
trabeculae in rodents relative to dogs and nonhuman primates.31
plays a crucial role in determining bone mechanical properties
Similarly, the cortical bone mineral density at the proximal fem-
and risk of fracture.32,34,46,52,58,68
oral diaphysis was slightly higher in mice and rat) and rabbits

82

cm10000070.indd 82 3/4/2011 1:38:57 PM


Figure 6. Radiographs of the mandible captured by (A) digital radiog-
raphy and (B) 2D and (C) 3D mCT images of the cross-sectional areas
made through the first or second molar as indicated by the dotted line.
(D) Cancellous bone parameters were measured in the areas beneath the
first or second molar indicated by the red squares.
relative to dog and cynomolgus macaques, possibly due to the
presence of Haversian systems and intracortical remodeling that
is seen in dogs and nonhuman primates but far less in rabbits
and rodents.15,30,40 Rodents, dogs, and cynomolgus macaques had
similar ratios of bone to tissue volume. As expected, larger spe-
cies had thicker cortex to maintain organ dimensionality in terms
of bone length and thickness and to ensure that the mechanical
demands imposed on the skeleton are met. As depicted in Figure
1, the proximal femur of dogs and cynomolgus macaques more
closely resemble the gross and microanatomy of the human proxi-
mal femur than does that of rabbits, rats, and mice and therefore
likely are better models for studying the physiology of the hu-
man proximal femur and hip joint. Even though the mechanical
loads in the proximal femur differ between humans and quad-
rupeds, and the reduced physical activity of laboratory animals
has an effect on biomechanical studies, the anatomic and struc-
tural similarities of the proximal femur and hip joint between
humans, dogs, and nonhuman primates allow for biomedical
research under laboratory conditions using dogs and nonhuman
primates.8,31,45,46,47,60,66 However, it should be remembered that bone
cm10000070.indd 83
Skeletal anatomy of lab animals
mass, gross and microanatomy are optimally designed to ensure
maximal safety of the skeleton during natural activities that are
unique for each species.5,63 Our study of skeletal variations among
laboratory animals indicates that absolute values recorded for
bone parameters cannot be directly compared between species.
Our data do not allow the conclusion that based on, for example,
higher bone mineral density or better connected cancellous struc-
ture, a skeleton in one species is superior to that in others.
The gross and microanatomic structure of the lumbar vertebrae
varies considerably among common laboratory species. Because
bone mineral density was fairly similar among all species, we be-
lieve that measurements of volumetric bone mineral density and
cancellous bone structure should be used for prediction of bone
strength at the lumbar spine.34,58 Because the mechanical loads on
the horizontal spine in quadrupeds differ from mechanical loads
in humans, in which the spine maintains an upright (vertical) po-
sition, biomechanical results and data describing structural bone
changes in the vertebral column of laboratory animals require
careful rationalization when extrapolating to the biomechanics in
humans.7,25,64,64 However, rat models can be used successfully to
provide valuable information regarding the physiology of long
bones and the spine, and diverse rat models and laboratory con-
ditions can be modeled further to better resemble the consequenc-
es of human osteoporoses on the skeleton.19,27,28,50,72
Although mechanical forces provide critical signals for bone
modeling and remodeling events throughout the skeleton, the
biomechanics of the jaws is unique and differs from that of
weight-bearing bones in the axial skeleton.4,67 During biting, a
complex pattern of stress and strains (compressive, tensile, shear,
and torsional) occurs in the jaws. The range and distribution of
mechanical loads varies among species but always depends on
the nature of the loads applied and the material properties and
geometry of the jaws.13,24 The occlusal force during biting is trans-
ferred from the teeth to the cancellous and cortical bone of the
jaws; even though its volume of trabecular bone is considerably
lower than that of cortical bone, the cancellous bone surrounding
the tooth socket plays a key role in tooth grafting and load distri-
bution. Moreover, trabecular structural change (damage) reflects
the fragility of bone tissue more directly than does a decrease in
bone volume; therefore, it is of the utmost importance to use ani-
mal models whose jaws reflect a cancellous bone distribution that
is similar to that of the human mandible.54,56,57
Numerous investigators have emphasized the lack of animal
models as a major impediment to supporting dental research asso-
ciated with bone loss in the jaws, which is known for its complex
pathogenesis and etiology.21,59 Attributes of the ideal model for
dental research would include anatomic and physiologic features
that are comparable to those in humans, systemic skeletal and
craniofacial disease progression resembling human conditions,
and an opportunity to study both systemic and local factors.59
Existing animal models all have advantages and disadvantages.
Rodents and rabbits are readily available and could be used to an-
swer some basic questions. However, they have substantial physi-
ologic and anatomic differences from humans and do not present
a good model for dental research, mainly due to the presence of
incisors and relatively small areas with cancellous bone.14,33,44 Of all
the species we investigated, rabbits seem to be the least desirable
model to study oral mechanics and pathophysiology for extrapo-
lation of data to humans because the incisors and rootless teeth of
rabbits are embedded deep into the bony parts of the mandible,
83
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 Vol 61, No 1
Comparative Medicine
February 2011
which contains very small areas of cancellous bone. Furthermore,
the presence of the incisors and small cancellous bone area greatly
limit the use of rodents to study madibular physiology. On the
basis of results from the current study, cynomolgus macaques
and dogs seem to be the models of choice for preclinical stud-
ies of periodontal disease and the dental effects associated with
bone loss because the bony structure of jaws and the anatomy of
molars mimic human anatomy and physiology; however, other
species including pigs might also be used in dental research.48
The size and shape of the mandibular corpus are linked function-
ally to the biomechanics of chewing and biting and therefore are
specific to species.11 In addition to bone mass and structure, other
relevant differences in form and function, including forces that
act on the mandible during mastication, exist between laboratory
animals and humans, and those differences should be weighed
when extrapolating data from animal studies to humans.
Taken together, the results of this study emphasize key param-
eters of the gross anatomy and microanatomy of the proximal
femur, lumbar spine, and mandible of commonly used laboratory
species. Combination of radiology and mCT allows for quick,
reliable, and noninvasive evaluation of bone morphology, the
complex microarchitecture of cortical and cancellous bone, and
bone mineral density, with great translational value from the
preclinical to clinical environment. The described skeletal char-
acteristics and human relevance suggest that rabbit seems to be
the least desirable species to conduct preclinical research of bone
physiology due to morphology of the proximal femur, including a
very short femoral neck and small amounts of cancellous bone at
femoral neck, vertebral body, and mandible, whereas cynomolo-
gus macaques likely are the most appropriate among the species
we studied. However, rodent models, particularly rat models,
are extremely useful for conducting basic research involving the
skeleton and represent a good and affordable alternative to dogs
and nonhuman primates. Even though direct comparisons be-
tween species are difficult and extrapolating the data obtained
to humans can be complex, we believe that a better depiction of
anatomic and structural characteristics of skeletal sites in the labo-
ratory species presented here will assist scientists in choosing the
appropriate animal models and skeletal sites that best support
their particular research. This choice may help researchers to re-
duce unnecessary work involving animals.
Acknowledgments
We thank all of our colleagues from Comparative Medicine and Drug
Safety Research and Development at Pfizer (Groton, Connecticut) for
their help when collecting the bones from laboratory animals.
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