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Estimated intracortical bone turnover in the femur of growing macaquesImplications for their use as models in skeletal pathology.

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THE ANATOMICAL RECORD 232:180-189 (1992)
Estimated Intracortical Bone Turnover in the Femur of Growing
Macaques: Implications for Their Use as Models in
Skeletal Pathology
Departments of Anatomy and Orthopaedic Surgery, Indiana University School of Medicine,
Indianapolis, Indiana 46202
Although macaques have been used widely to study the dynamics
of bone remodeling, there have been few comparisons to skeletal tissue turnover in
humans. This study analyzes variation in bone microstructure with respect to
gender, age, and body weight in growing macaques to determine whether the
pattern of osteonal remodeling in macaques is like that in analogous bones of
humans. Histomorphometric measurements were made on femoral midshaft crosssections of 54 macaques from the Cay0 Santiago skeletal collection. These data show
that variation in bone microstructure occurs independent of gender, age, and body
weight in macaques. Moreover, intracortical bone turnover in the macaque femur
is much slower than in humans, making them poor models to study the effects of
weightlessness, but good models to study low turnover skeletal dysplasias.
The use of animal models to study human disease
permits study of the disease while controlling all relevant variables that could affect it. Nonhuman primates
are particularly useful because of their taxonomic affinities to humans. Macaques in particular have been
used widely for biomedical studies of skeletal pathology (Bowden, 1979; Cann et al., 1980; Young and
Schneider, 1981; Williams and Bowden, 1984; DeRousseau, 1985; Turnquist, 1983, 1985; Jerome et al., 1986;
Young et al., 1986; Simmons et al., 1984, 1986; Miller
et al., 1986). Remarkably, in view of their widespread
use in biomedical research, we know relatively little
about the processes of bone remodeling at the tissue
level in these animals. Only a few studies have examined remodeling kinetics in rhesus macaques (Schock
et al., 1972,1975; Przybeck, 1985). These studies have
not examined the gender or body weight variation in
relation to skeletal dynamics. Furthermore, variation
has been incompletely characterized using only 2-3
samples at discrete age intervals.
Preliminary data that suggested that the rate of intracortical bone turnover in macaques is quite low
(Schaffler and Burr, 1984; Burr et al., 1989) support
the contention that macaques may provide relatively
good models for some human skeletal disease, e.g., senile osteoporosis. The broad objective of this work was
to discover whether the processes of skeletal remodeling during maturation in rhesus macaques are like
those in growing humans, allowing Macaca rnulatta to
be used as an animal model for diseases that involve
abnormal remodeling physiology. Several specific
questions were posed:
1. Does variation in bone microstructure occur independent of gender, age, andlor body weight?
2. Are growing macaques different than adult
macaques or adult humans in the extent of intracortical bone remodeling?
3. Are there maturational effects on bone remodeling in growing macaques that create different age-adjusted values for variables that describe remodeling in
males and females?
It is desirable to know something about the mechanical environment to which bone is exposed. Peak principal strain magnitudes and distribution have been collected in vivo in nonhuman primates only for the
macaque mandible (Hylander, 1981, 1984) and tibia
(Young et al., 1977) and for gibbon upper limb bones
(Swartz et al., 1989). The midshaft of the femur in M .
mulatta provides a site that 1) can be accurately defined in different animals; 2) is mechanically relevant
and “comparable”across species; and 3) can be mechanically analyzed using beam theory even prior to collection of relevant in vivo strain data. All these reasons
make this site suitable for analysis.
One millimeter thick cross-sections were removed
from the femoral midshafts of Cay0 Santiago derived
M . rnulatta (n = 31 females and 23 males) ranging in
age from 1.5-8.0 years of age. All femoral epiphyses
are fused by 5.25 years in female and 6.0 years in male
M . rnulatta (Cheverud, 1981). As these are among the
last long bone epiphyses to fuse, this can be considered
the age of skeletal maturity in this species. The mean
age of males (4.57 2 1.79) was not significantly different than that in females (4.28 1.91). Only animals
with known body weights were used. Body weights
were taken from the medical records kept a t the Caribbean Primate Research Center (CPRC) in Puerto Rico.
All animals had been born free-ranging on Cay0 Santiago, an island off the southeast coast of Puerto Rico,
Received February 8, 1991; accepted June 19, 1991.
but transferred to enclosures a t Sabana Seca in the
CPRC at varying periods prior to death. Medical
records were evaluated for all animals. Most animals
had died as the result of wounds received from other
animals, or of parasitic infections. We used no animals
that died of metabolic diseases.
The cross-sections were glued with cyanoacrylate to
a plexiglass slide and hand ground to 150 microns thick
using 600 grit silicon carbide paper, acid etched with
HC1, and stained with toluidine blue. This makes identification of the cement line easier and facilitates identification of secondary osteons as distinct from primary
osteons and vascular spaces. Secondary osteons represent remodeled bone and are defined by the presence of
a cement line. Primary osteons represent the primary
infilling of vascular spaces, are not replacement bone,
and as such, have no cement line. Sections were viewed
a t x212 magnification using a Zeiss Universal Research microscope.
The sections were examined quantitatively using a n
IBM-PC XT microcomputer and Bioquant image analysis software. Only secondary osteons were measured
and the following calculations used for analysis:
tant determinant of variation in osteon development.
To investigate the nature of this possible size-related
source of variation, allometric equations (y = bxk)
were calculated on log-transformed variables. The exponent of each relationship was estimated by both
model I (least squares) and model I1 (major axis) regressions. Major axis (principal axis) fits to the logtransformed data acknowledge the fact that both x and
y variables possess associated error terms, and estimates of the exponent k tend to be slightly higher than
least squares values. Both regression models yield virtually identical results and inferences when the correlation between x and y variables is reasonably high.
Because intraspecific allometric analyses with weight
tend to have low correlation coefficients, reduced major
axis (RMA) regression analysis may be preferable to
either major axis or least squares methods (Rayner,
1981; Seim and Saether, 1983; Ricker, 1984). RMA fits
to the data were also explored. Analysis of covariance
was used to determine interactive effects of gender on
this relationship.
Values for all individuals for each of the variables
were examined in multivariate space using the interactive statistical graphics package J M P (SAS Institute,
1. Percent osteonal area = (total summed osteon Inc., Cary, NC). Three individuals were outliers on several variables. These individuals “leverage” the rest of
arealcortical area) x 100.
2. Osteons/mm2 (#/mm2): the number of osteons the data, artificially increasing the r2 value for a given
with intact haversian canals per unit area of bone.
regression. This can be misleading by suggesting a
3. Osteon fragmentdrnm’ (#/mm2): the number of strong relationship between variables when none expartial osteons without haversian canals per unit area ists. To avoid this, we adopted the conservative approach, and eliminated these three individuals (2
of bone.
4. Osteon population density/mm2 (OPD, #/mm2): males, 1 female) from the analysis. Two of these individuals were among the youngest (less than 2 years
the sum of 2 and 3.
5. Mean osteon area (Ao, pm2): areas within the 0s- old) and we felt that the small amount of bone in the
teonal cement line, measured for each osteon in a cross- cross-section could have biased the OPD counts.
Analysis of covariance was used to assess differences
section and averaged.
6. Mean wall thickness (MWT, pm) = ([osteon area in microstructure with respect to gender, age, and body
weight. Linear regression analysis was used to deter- canal area]*2)/(osteon perimeter + canal perimeter); the average distance from cement line to haver- mine whether microstructure changed in linear fashsian canal wall. We use this method to avoid bias in- ion with age. Polynomial fits to the data were also introduced by relating to what location in a n osteon to vestigated. Finally logistic regression analysis was
measure. According to Quarles and Lobaugh (1989) employed to further examine changes in bone microthickness can be measured either directly or indirectly structure with age.
with the same error. Direct linear measurements rely
on the observer’s ability to randomly choose sites for
With Body Weight
measurement in osteons that are not completely circuAs expected, body weight and age in growing
lar. The method employed here eliminates bias by avmacaques are strongly correlated (Fig. 1; r2 = .79 to
eraging all possible MWTs for a given osteon.
7. Activation frequency (mu, #/mm2/year) = OPDI predict age from weight, and .82 to predict weight from
mean tissue age; this is the number of osteon creations age; P < .0001). The relationship between age and
per unit time. Because the mean tissue age is not weight is different in male and female macaques, as
known for these animals, and because the OPD is so demonstrated by significant interactions of each with
small, we assumed t h a t mean tissue age = chronolog- gender (P < .01 and P < .03, respectively).
Table 1 shows that the only microstructural variical age.
8. Bone formation rate (BFR, mm2/mm2/year) = ables that can predict body weight a t any acceptable
confidence level are variables that are calculated using
(mu * A,)/106
age (mu and BFR). Other than these, mean osteon area
Wu et al. (1970) described the methods used to cal- is the best predictor, but explains only 34% of the variculate activation frequency and BFR from cross-sec- ation in weight. Except for percent osteonal bone, no
tions without intravital labeling. Frost (1987 a,b) ex- interactive effects with sex were found when micropanded on the mathematical justification for these structural variables were regressed on body weight,
measurements. The basis for the other measurements suggesting that gender is not a n important factor in
is more fully described by Stout and Teitelbaum (19791, relationships between microstructure and weight.
Activation frequency and BFR vary inversely with
and Schaffler and Burr (1984).
Within a taxonomic group, weight may be an impor- body weight (b = -1.33 and -1.09, respectively for
macaques, both in laboratory and free-ranging settings. Logistic regressions showed that each microstructural variable predicted less than 6% of the variation in age. Because osteons do accumulate with age
(at least in humans), logistic regressions using percent
osteonal bone and OPD in combination were computed.
These two variables together accounted for only 8% of
the variation in age.
Variation of Microstructure With Gender
Fig. 1. Regression of age (years) vs. weight (kilograms) for growing
macaques showing the strong correlation between the two (rz = .79).
Age = .67-.22 (weight). The solid line represents the best least
squares fit to the data, and the broken line represents one standard
deviation about this line.
Using either chi square or analysis of variance, no
significant differences in bone microstructure were
found between males and females (Table 3a,b). Males
had larger mean osteon sizes and smaller OPD, but
these were not significantly different than those in females. These data indicate that gender cannot be determined based on changes in bone microstructure.
Covariance analysis highlighted no interactions between age and gender for any microstructural variable.
At least as far as bone remodeling is concerned, females do not mature at a rate different than that in
Differences in Microstructure in Growing
and Adult Macaques
The proportion of remodeled cortex is significantly
greater in growing macaques than in adults, suggesting that apposition of primary lamellar bone may continue with age in macaques although remodeling of
RMA fits), probably because of the strong relationship this new bone slows (Table 3a,b, Fig. 2). The percent of
between weight and age in these growing animals. The remodeled cortex decreases after maturity because the
relationship decreases exponentially with age, indicat- osteonal bone near the marrow cavity, having the
ing that osteons do not accumulate very rapidly with greatest mean tissue age, is preferentially removed.
maturation. This is reflected in the association be- The OPD in adult macaques, however, is greater than
tween weight and the percentage of cortex occupied by in growing animals (Fig. 31, although no significant
osteons (Table 1). Least squares fits show that the linear relationship exists between OPD and age within
amount of remodeled cortex increases at only 5%of the the age range we studied (Fig. 4). We do not have data
rate a t which the animals gain weight. Even RMA fits for osteon size in adult macaques, but the inverse reshow that the remodeled cortex increases at only 75% lation of OPD with percent of remodeled cortex can
of the rate of weight gain. The OPD, however, de- only be possible if osteons become smaller with age.
creases with weight gain (b = -0.26 for least squares
Figure 5 shows bone microstructure a t the femoral
fits and -0.83 for RMA fits; Table 1).
midshaft in immature (1.8 years), young adult (6.1
The larger amount of remodeled cortex, but fewer years), and old (25 years) male macaques. These photoosteons, means that osteons become smaller as ma- micrographs also demonstrate that osteons do not accaques mature. This is indeed born out by inspection of cumulate with age in M . mulatta.
the data (Table 1). Mean osteonal area increases at
Differences in Microstructure in Macaques and Humans
about one-third the rate that weight increases (r2 =
.34; b = 0.43, RMA fit).
Table 3a,b and Figures 2 and 3 clearly show that the
potential for intracortical bone remodeling in maVariation of Microstructure With Age
caques is less than that in humans. The proportion of
Age accounts for little of the variation in the micro- femoral cortex that is remodeled t o secondary osteons
structural variables examined (Table 2). Except for is much lower in both growing and mature adult
those variables that are calculated using age (mu and macaques than it is in the human femur. Adult
BFR), age predicts less than 20% of the variation in macaques have less than half the OPD found in adult
each of the microstructural variables (r2 < .15). Age human femurs; growing macaques have even less.
predicts mean osteonal size better than it predicts the
other variables (r2 = .15, P < .005), but the relationship is still far from linear.
The need t o develop primate models to study the tisUsing polynomial fits to the data, age predicts 21- sue level effects of human skeletal physiology dictates
34% of the variation in the variables (Table 2 ) , again that normal bone remodeling during skeletal maturaignoring variables that use age in their calculation. tion be studied in some primate species. The extent to
These fits are all statistically significant, a t P < .02 or which genetically determined developmental effects
predominate over metabolic or mechanical influences,
In humans, bone microstructure has been used to or how these factors might interact to produce the final
predict age. This could be potentially useful in adult morphology, is not known.
TABLE 1. Summary of regression fits for body weight vs. microstructure’
% Osteonal bone
Mean area/osteon ( x
Activation frequency
Least squares fit
Major axis fit
RMA fit
‘All data were log transformed. Least squares regressions were computed using the standard form of the allometric equation, log y = log a +
b log (wei ht) The slope for least squares is defined as S , ISxx;the slope for major axis regressions is defined by 1/2S [S - S,, + ([S - S,,I2
+ 4SX,2)’?.’, the’ slope for RMA regression is defined by C~yJS,,)”2 when S,, > 0, or the negative of this when S,, 2 0 . m e intercept E always
defined as y -slope x. The r-value is the same for all regression fits.
*P < .05.
**P < .01.
TABLE 2. Summary of regression fits for age vs. microstructure’
% Osteonal bone
Mean area/osteon(x
Activation frequency
Least squares fit
Polynomial fit
- 1.03**
- 1.63**
‘Least squares regressions fit the equation y = a + bx, where y is the microstructural variable, x is the age, a is the intercept, and b is the
slope. Polynomial regressions fit the equation y = a + b,x + b,x2.
*P < .05.
**P < .01
Some skeletal diseases depress intracortical bone formation, while a t the same time increasing formation
along the periosteal surface (Wirth et al., 1982). These
include some skeletal dysplasias found primarily in
growing children, and also more common afflictions of
age such as senile (type 11) osteoporosis. Intracortical
activation frequency appears to be normally depressed
in rhesus macaques. M. mulatta may prove to be a reasonable model for skeletal pathologies in which osteonal activation rates are slow, but a poor model to
study the effects of rapid turnover.
Probfems in Calculating Activation Frequency From
Nonlabeled Bone
The calculation of activation frequency from nonlabeled bone assumes that the mean age of the tissue is
known. This is a function both of the amount of time
osteons have been accumulating and the rate a t which
osteons are lost from view. Underlying this is the assumption that OPD increases with age, at a rate determined by activation frequency. In other words, the activation frequency is the slope of the regression line
between OPD and age. If OPD decreases with age, this
assumption is violated, and the calculation of a n accurate activation frequency may be invalid.
The slope of the regression line of OPD on age is
negative (Table 2), suggesting that OPD decreases
with age in macaques, and calling into question the
validity of the activation frequency calculation. However, this decline is statistically insignificant, as is the
r2 value, and Figure 4 shows that no true inverse relationship exists. Moreover, OPD is greater in mature
macaques than in growing ones (Table 3a,b, Fig. 3)
suggesting a n overall age-related increase in OPD. In
view of these facts, the calculation of activation frequency in this sample of growing macaques is probably
valid and is a n accurate reflection of the actual activation frequency.
Is Variation in Bone Microstructure Independent of Gender,
Age, and Body Weight?
In a previous experiment, we observed a convergence
between bone microstructure in the femur of a series of
primates and the movement patterns of these primates
defined kinesiologically (Schaff ler and Burr, 1984).
These observations led us to hypothesize that the nature of the mechanical stimulus is an important determinant of bone morphology a t the microstructural
level. This seemed reasonable because it is well known
that mechanical stimuli control bone remodeling
(Frost, 1983, 1987c,d; Rubin and Lanyon, 1984, 1985;
Pead et al., 1988; Lanyon et al., 19821, and osteon formation is the result of bone remodeling events within
the cortex. We concluded that the amount of osteonal
bone is a n indicator of how a n animal uses its limbs.
There are many influences on bone besides mechan-
TABLE 3a. Histomorphometric data for macaque and
human femur and rib'
FragOsteonal Osteonsi mentsi
(#imm') (#/mm')
Immature macaque
Immature macaque
Immature macaque
(4-8 years)
OPD (#/mm /
(pm2) (#/mm')
(0.75) (15.89)
(1.48) (11.13)
TABLE 3b. Histomorphometric data for macaque and
human femur and rib'
'Numbers in parentheses are standard deviations.
'Data from current study; n = 31 female and 23 males; Mean ages =
4.28 and 4.57 years, respectively.
3Schaffler and Burr, 1984; n = 1; M . muluttu; age unknown.
4Evans, 1982; n z 54 specimens from 16 individuals (12 males and 4
females) ranging in age from 33-98 years, mean age = 64.81 years.
'Evans, 1976; n = 35 (mean age = 41.5 years).
'Przybeck, 1985; n = 6; age 4-8 years, mean age = 6.0 years.
7Schock et al., 1972; based on tetracycline labeling data in ribs from
13 macaques ages 3.5-4.6 years (mean age not given but we estimate
it at approximately 4.22 years).
'Wu et al., 1970; data from the ribs of growing humans combine age
groups 0-9 years (mean age = 6.0 years, n = 24) and 10-19 years
(mean age = 15.80 years, n = 25); bone formation rates are calculated
from OPD and tetracycline labeling data, respectively.
'Przybeck, 1985; n = 9; age 13-31 years, mean age = 22.67 years.
'OSchock et al., 1975; based on tetracycline labeling data from 23 late
adolescent male rhesus macaques (specific ages not provided).
"Pirok et al., 1966; n = 226 males (ages 0-71-t years; mean age =
37.17 years) and 147 females (ages 0-71 years, mean age = 35.26
ical ones. It is possible that other influences contributed to the correlation of movement pattern and bone
microstructure. Before we could conclude that microstructure and limb usage were related, it was necessary to address the normal variation related to differences in age, gender, and body weight that could
significantly influence the microstructure of bone.
Data from the present study suggest strongly that variation in bone microstructure occurs independent of
variation in body weight, age, and gender in growing
macaques. Moreover, there are no maturaticnal effects.
Age-matched male and female macaques have comparable bone microstructures.
Intraspecifically, body weight is not a n important
determinant of OPD, although weight may be related
to osteon size (Table 1).The implication of this is that
increased body size has no effect on the initiation of
new remodeling sites (i.e., the activation frequency and
the rate of bone turnover), but does have some effect on
the individual vigor of osteoblasts and osteoclasts. As
in growing humans, i t suggests a decreasing individual
cell level activity for osteoclasts with the onset of ma-
Immature macaque
Immature macaque
Immature macaque
(4-8 years)
1.88' 0.034'
(1.87) (0.029)
1.26' 0.026'
(0.87) (0.012)
17.316 0.4356
(10.82) (0.26)
27.907 0.3607
(13.00) (0.18)
13.705 0.45g5
10.00~ 0.210~
(5.00) (0.151
8.78' 0.186'
(2.32) (0.07)
2.67' 0.08810
'Numbers in parentheses are standard deviations.
'Data from current study; n = 31 females and 23 males; mean ages =
4.28 and 4.57 years, respectively.
3Larson, unpublished manuscript, 1986; n = 12; age not specified.
4The mean of data from Currey, 1964 (ages 23-89 years, mean age =
57.47 years), Jowsey, 1966 (ages 20-90 years, mean age not specified);
and Martin et al., 1980 (ages 37-96 years, mean age = 69.26 years);
n = 65.
%tout and Gavan, unpublished manuscript; n = 104.
'Przybeck, 1985; n = 6; age 4-8 years, mean age = 6.0 years.
7Schock et al., 1972; based on tetracycline labeling data in ribs from
13 macaques ages 3.5-4.6 years (mean age not given but we estimate
it at approximately 4.22 years).
'Wu et al., 1970; data from the ribs of growing humans combine age
groups 0-9 years (mean age = 6.0 years, n = 24) and 10-19 years
(mean age = 15.80 years, n = 25); bone formation rates are calculated
from OPD and tetracycline labeling data, respectively.
'Przybeck, 1985; n = 9; ages 13-31 years, mean age = 22.67 years.
"Mean of Stout and Gavan, unpubished manuscript; and Wu et al.,
"Parfitt, 1983, age not given.
''Pirok et al., 1966; n = 226 males (ages 0-71 + years; mean age =
37.17 years) and 147 females (ages 0-71 years, mean age = 35.26
turity. Because MWT did not also decline (Tables 1,a),
osteoblastic refilling of resorption cavities is not affected. Decreased osteon area without a n accompanying change in MWT implies that osteoclasts are less
active or fewer in adult macaques, and that the intracortical resorption-formation balance shifts in greater
favor of formation as maturity is reached. The decline
of OPD during development supports the idea that
fewer BMUs are activated as adolescent monkeys ap-
‘ o c t
Fig. 2. The amount of femoral cortex remodeled in adult macaques
is less than 25% of that in humans, indicating the conservative nature
of intracortical bone turnover in macaques. The proportion of remodeled cortex actually declines in adult macaques, suggesting that remodeling of the cortex does not keep pace with apposition of new
periosteal lamellar bone. Data for adult macaques are from Schaffler
and Burr (1984), while those for adult humans are from Evans (1982).
Standard errors are not reported by Evans. Data for adult M . mulutta
are based on a single sample because these are the only data available, although several other macaque species were examined by
Schaffler and Burr (1984) with similar results.
Fig. 3. OPD in the femoral midshaft is greater in adult macaques
than in growing macaques. However, there are still fewer than half as
many osteons in adult macaque femurs as in adult human femurs.
Intracortical remodeling in the macaque femur is more conservative
than in the rib, where OPD is greater than in humans. Data for adult
humans and adult macaques were taken from Larson (unpublished
material) (n = 12 macaques) and Stout and Gavan, (unpublished
material) (n = 104 humans).
proach skeletal maturity. This also means that, in a
global sense, fewer osteoclasts are recruited.
Significant cortical-endosteal resorption tends to remove the larger osteons found close to the marrow cavity and skews the osteon population toward smaller
sizes (Takahashi et al., 1965). A process like this occurs
in adult humans as well (Currey, 1964; Landeros and
Frost, 1964; Jowsey, 1966; Hattner et al., 1964). As ent in growing and adult primates from the genera
cortical-endosteal resorption and periosteal apposition Ateles and Pan. Data presented here suggest that the
occur with age, osteonal bone is destroyed near the rate of accumulation of osteons in growing macaques
marrow cavity and replaced with nonosteonal bone does not change significantly with age. The trend
periosteally. This process cannot fully account for the throughout the growth years is for no change in the
changes observed in growing monkeys. Although it amount of remodeled cortex (Table 2). The OPD is
would reduce the number of osteons per unit area of greater in adult macaques, as expected and as observed
bone, it would also reduce the percentage of bone cortex in humans and other species (Currey, 1964; Atkinson,
occupied by osteons. The amount of remodeled cortex 1965; Kerley, 1965; Evans and Bang, 1967; Singh and
did not decrease in growing macaques. Moreover, the Gunberg, 1970; Ortner, 1975; Martin et al., 1980), alincrease in cross-sectional area levels off a t about 6 though OPD never approaches that in humans, even in
years in both male and female macaques. Therefore, old animals (Fig. 5). Data from growing macaques are
between 6 and 8 years there is not much periosteal consistent with data from adult macaques in suggestapposition of primary lamellar bone that could skew ing some inhibition on intracortical bone remodeling
the results. In combination, this suggests a real decline processes relative to humans.
in activation frequency, although perhaps a smaller
Are Macaques Different Than Humans in the Extent of
decline than indicated by the data.
Osteonal Remodeling?
Are Growing Macaques Different Than Adult Macaques in
the Extent of Osteonal Remodeling?
In previous work (Schaffler and Burr, 1984) we observed that the accumulation of osteons was not differ-
There are limited data about activation frequency
and BFR from the femur of any nonhuman primate,
and most of the data for humans come from the rib or
iliac crest. Comparative data are sketchy. The data we
P 5
Fig. 4. Regression of OPD (#/rnrn2) vs. age (years) for growing
macaques showing no relationship between the two variables (r2 =
.07). OPD = 9.05 - 0.61 (age). The solid line represents the best least
squares fit to the data, and the broken lines represent one standard
deviation about this line.
have collected for the femoral midshaft are unique for
that bone.
Rhesus macaques have been used to study the effects
of reduced loading on bone (Schock et al., 1975; Young
and Schneider, 1981; Young et al., 1983,1986; Wronski
and Morey, 1983) partly as a means to evaluate the
effects of hypogravic environments on skeletal physiology. One reason for using macaques is that they represent an animal taxonomically closer to humans than
dogs or rats. A good model for human skeletal physiology requires that the rate at which bone remodeling
can be activated, and the resulting bone morphology,
are also like those in humans. The data presented here
suggest that intracortical remodeling in the long bones
of macaques is distinct from those same processes in
older humans. Although good information does not exist on the BFR in adult macaque or adult human femora, the low OPD suggests that the intracortical BFR
in macaques is significantly lower than that in humans.
It is possible that the reason that humans appear to
have a greater OPD and higher BFR is that osteons
have had a longer period over which to accumulate.
Macaques in this study have had less than 8 years to
accumulate osteons, whereas the humans we surveyed
had 40-90 years. However, our data suggest that osteon accumulation is unlikely to be solely a function of
age. There is little correlation between age and proportion of remodeled cortex (Fig. 2). OPD in the femur is
only slightly greater in adult macaques than in immature macaques (Fig. 3). Moreover, Figures 5e,f clearly
show the absence of an osteonized femoral cortex even
in a 25 year old macaque. This is an age at which there
is no question that human bone has a high OPD. OPD
in the rib is greater than that in adult humans, suggesting that the low OPD in macaque femora may be
less a function of an inherent inability to form osteons,
than a locally conservative BFR in the macaque femur.
Finally, data from Jowsey (1963) shows that human
bone is heavily osteonized even by the age of 2 years.
Clearly, better data is needed for younger humans and
for older macaques before the issue can be resolved.
Stout and Gavan (unpublished manuscript) and Larson (unpublished manuscript) observed depressed intracortical bone remodeling in the macaque femur.
Likewise, Schock et al. (1975) found that immobilization in rhesus monkeys did not evoke an increased remodeling space. There was no increased activation frequency following 2 months of immobilization. This is
contrary to the observation in humans that immobilization for even short periods of time significantly elevates the activation frequency for intracortical bone
remodeling and alters global bone balance (Heaney,
1962; Minaire et al., 1974; Stout, 1982; Chantraine et
al., 1986).
The significance of these observations is that
macaques may make poor models to study normal human skeletal tissue kinetic processes, and may not accurately reflect the extent to which bone can be lost in
the weight bearing bones in hypogravic environments.
The inhibition of remodeling activation would slow the
loss of bone and lead to an underestimate of the severity of bone loss. However, macaques may make ideal
models to study certain human skeletal pathologies,
including age-related osteoporosis in which cortical
bone turnover is depressed.
It is important to understand that these observations
apply only to cortical bone, and only to the intracortical
envelope. As such, they do not speak to differences between macaques and humans in rates of formation or
resorption drifts that may occur on cortical-endosteal
and periosteal surfaces as a function of modeling processes, but apply only to intracortical remodeling. In
disuse, and in many metabolic bone diseases, significant bone loss occurs through modeling processes on
trabecular and cortical-endosteal surfaces as well.
Bone turnover rates on these envelopes are greater
than intracortically, and it is possible that the dynamics of these surfaces in the macaque more closely approximate those in humans. Direct comparisons between trabecular bone dynamics in humans and
macaques have never been made, but are needed.
These data paint quite a different picture of bone
remodeling in macaques than data collected from rib
biopsies. Przybeck (1985) found OPD in the macaque
rib was 60% greater than OPD in the human rib, and
that remodeling rates were comparably high (Fig. 3).
Using intravital tetracycline labels, Schock et al.
(1972) measured formation rates in juvenile monkey
ribs that were 1.7 times greater than in juvenile humans. Based on these observations Przybeck (1985)
suggested that macaques might represent excellent
models for human bone remodeling. The reasons for the
differences between rib and femur are unclear. They
may be related to specific local factors (relationships of
periosteum or marrow to bone cortex, for example), relative relationships of cortical and trabecular bone, or
reflect different mechanical environments.
Fig. 5. Photomicrographs showing that osteons do not accumulate
with age in macaques. In each case, the higher power photomicrograph was taken from the region of the femur that had the most
secondary osteons. The few secondary osteons that exist are confined
to the bone with the oldest mean tissue age, i.e., near the cortical-
endosteal surface. The remainder of the cortex is composed of primary
lamellar bone and primary vascular spaces. The box on the low power
photomicrograph highlights the area from which the higher power
micrograph was taken. (a,b) 1.8 years, x 9.5, x 50; (c,d) 6.1 yrs.,
x 6.3, x 32; (e,D 25 years, x 6, x 32 (on overleaf).
1. Variation in bone microstructure occurs independent of gender, age, and body weight in growing
2. Microstructure of the femoral midshaft cannot be
used to estimate age or body weight in macaques in
which these life data are unknown.
3. Bone turnover in the femur in macaques is much
slower than in humans. Because of this, macaques
probably make poor models to study the effects of
weightlessness, but may make good models to study
low turnover skeletal dysplasias.
4. Remodeling rates in macaque rib and femur are
significantly different, suggesting that local factors
control bone formation rate to a significant degree.
This research was supported by NIH grant P40RRO3640-04 to the Caribbean Primate Research Center (Project I1 (El 4) and by NIH grant AR 39708. I wish
to thank Satoshi Mori for preparation of the photomicrographs, Cary Johnson for help with tissue preparations, and Terri Stafford for help with microscopic analysis, and to express my gratitude to Jean Turnquist,
Matt Kessler and the Caribbean Primate Research
Center for access to the Cay0 Santiago-derived skeletal
collections and for laboratory facilities. My appreciation is also extended to Bill Jungers for explaining the
basis for various regression fits to the data, and to
Bruce Martin and Harold Frost for reading and criticizing the manuscript prior to submission.
Fig. 5e-f
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