Endocrinology Vol. 139, No. 8 3399-3403
Copyright © 1998 by The Endocrine Society
Tamoxifen Attenuates the Effects of Exogenous Glucocorticoid on Bone Formation and Growth in Piglets1
P. C. Fritz,
W. E. Ward,
S. A. Atkinson and
H. C. Tenenbaum
Medical Research Council Group in Periodontal Physiology, Faculty
of Dentistry, University of Toronto, Toronto, Ontario, Canada M5G 1G6;
and the Department of Pediatrics, McMaster University, Hamilton,
Ontario, Canada L8N 3Z5
Address all correspondence and requests for reprints to: Dr. H. C. Tenenbaum, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ontario, Canada M5G 1G6. E-mail:
htenenbaum{at}dental.utoronto.ca
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Abstract
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Tamoxifen (Tam) has been shown to inhibit dexamethasone (Dex)-mediated
effects on bone formation in vitro. Our objective was to
determine whether Tam would block Dex-induced osteopenia and growth
inhibition in growing piglets. Four-day-old male Yorkshire piglets were
adapted to a liquid formula diet (400 ml/kg·day) and randomized to
one of four groups (n = 5/group): Dex (0.5 mg/kg·day), Tam (1
mg/kg·day), Dex plus Tam, or placebo control (vehicle only). Both
drugs were administered by orogastric gavage twice daily for 12 days.
At baseline and at the end of treatment, whole body bone mineral
density (BMD) was determined by dual energy x-ray absorptiometry
(Hologic QDR1000W). Plasma osteocalcin and PTH were measured on days 0
and 12, and urinary N-telopeptide was measured on day
12. Changes in axial length and daily weight were also measured. Delta
whole body BMD was 29% lower (P < 0.05) in Dex
alone treated piglets than in controls (0.033 vs. 0.047
g/cm2, respectively), whereas the maximum change in BMD in
Dex plus Tam group (0.046 g/cm2) was similar to that in
controls. Concurrent Tam administration reduced the Dex-induced deficit
in weight gain by 56% (P < 0.05) and the deficit
in axial length gain by 72% (P < 0.01). In Dex
alone treated piglets, PTH was significantly elevated (7-fold), whereas
osteocalcin and N-telopeptide were significantly reduced
compared with control values. These effects were prevented by Tam.
These data suggest that the suppression of growth and other changes in
parameters of bone metabolism induced by glucocorticoids in
vivo can be attenuated by Tam.
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Introduction
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STEROID-INDUCED osteoporosis is well
described in adults (1), children (2, 3), and premature infants (4) who
receive exogenous glucocorticoid for its antiinflammatory action. In
infants and children, the effects of steroids extend to reductions in
somatic growth and bone mass (4, 5). As steroid treatment is often the
most effective treatment for managing many diseases, clinicians are
faced with the challenge of looking for concurrent therapies that may
prevent or lessen the negative side-effects of steroids in these
patients.
Steroids exert their effects on bone through many different mechanisms
(6). Addition of dexamethasone (Dex) to marrow-derived stromal cells
and chick periosteum culture systems has been shown to stimulate
osteoblastic differentiation (7, 8). However, with prolonged treatment
with Dex, osteoprogenitor reserves are depleted, and cells ultimately
lose their capacity to form bone (9). The addition of tamoxifen (Tam),
an estrogen analog, to these same culture systems prevented most
Dex-induced actions on bone formation (10). Moreover, studies in our
laboratory have demonstrated that another sex steroid antagonist,
RU38486, will inhibit glucocorticoid effects on bone in
vitro (11). There is also evidence that RU38486 may have the
capacity to reduce postovariectomy bone loss in rats (12).
Although the above-described findings were developed using bone cell
culture systems, we wished to explore whether Tam might exhibit
antiglucocorticoid effects on a wider array of parameters in
vivo. Thus, we chose to focus not only on bone growth and density
but also on indirect measures of bone metabolism (PTH and osteocalcin).
In addition, we studied whether Tam might attenuate the Dex-induced
reductions in parameters such as growth velocity and axial growth.
We hypothesized that glucocorticoids, sex steroids, and even the sex
steroid antagonists might coregulate each other’s actions on bone or
other tissues. With these ideas in mind, an in vivo study
was designed to determine whether glucocorticoid-induced effects on
somatic growth, with a specific focus on skeletal metabolism, could be
attenuated by concurrent administration of Tam. We chose to use the
Dex-treated piglet model because piglets have been shown to develop
bone abnormalities after a short course of Dex at a clinically relevant
dose (13).
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Materials and Methods
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Animals
Four-day-old male noncastrated Yorkshire piglets (n = 20)
were removed from the sow at the Arkell Swine Research Station (Guelph,
Canada), transported to the Central Animal Facility at McMaster
University, and randomized to one of four treatment groups: placebo
control, Tam alone, Dex alone, or Dex plus Tam. Piglets were housed
singly in steel metabolic cages maintained at 28 C using heat lamps and
kept on a 12-h light, 12-h dark cycle. Piglets were adapted to a liquid
diet (13) by providing 50% strength formula for the first 24 h,
followed by 75% and 100% strength formula on consecutive days. The
total formula provided was 400 ml/kg·day and divided over four feeds
during the day; 24-h formula intake was monitored. Piglets were allowed
to exercise twice daily and socialize for 1 h outside their cages
in a fenced pen. This protocol was approved by the animal ethics
committee at McMaster University.
Drug administration
Administration of Dex (0.5 mg/kg·day as a sodium phosphate
salt; Hexadrol, Organon, Toronto, Canada) and Tam (1 mg/kg·day as a
citrate salt; Sigma Chemical Co., St. Louis, MO) occurred twice daily
(0900 and 1700 h) by orogastric gavage technique (no. 8 French
tube) for 12 days (the Tam dose was determined in pilot studies). On
day 12, piglets were killed by lethal cardiac injection (Euthanol)
while under isoflurane anesthesia (AErrane, Anaquest, Mississauga,
Canada).
Anthropometry
Weight was measured each morning using an electronic scale
(Sartorius, Gottingen, Germany) with an animal-weighing program. Snout
to rump length was measured by the same person (P.C.F.) using a
nonstretchable plastic measuring tape each time the piglets were
anesthetized for blood sampling (days 0 and 12).
Blood and urine collections
Fasting blood samples were obtained by blind stab technique from
the external jugular between 0800–0900 h at baseline (day 0) and by
cardiac puncture at necropsy (day 12). Blood was collected in
heparinized tubes and centrifuged immediately for 20 min at 3000
x g at 4 C. Blood samples were stored at -70 C until
analyses were performed. A spot urine sample was obtained at necropsy
by removing urine directly from the bladder with a syringe. Urine
samples were frozen and stored at -20 C until analyses were
performed.
Biochemical markers of bone metabolism
Urinary N-telopeptide (NTx) of type I procollagen was
measured using a commercially available competitive inhibition
enzyme-linked immunoabsorbent assay (Osteomark, OSTEX, Seattle, WA).
Sample NTx competes with NTx coated in the microwells to bind a
purified murine monoclonal antibody that is conjugated to horseradish
peroxidase. The intra- and interassay coefficients of variation (CVs)
were 2.8% and 5.7%, respectively. NTx measurements were expressed as
a function of creatinine excretion that was measured by a colorimetric
assay (Procedure 555, Sigma). Intra- and interassay CVs for creatinine
were 3.4% and 2.5%, respectively. Plasma osteocalcin was measured
using a commercially available competitive RIA (Incstar Corp.,
Stillwater, MN). The plasma sample and [125I]bovine
osteocalcin competed for binding with a rabbit antibovine osteocalcin
antibody that is precipitated by a goat antirabbit serum. All plasma
samples were analyzed in duplicate and some in triplicate for
calculation of the intraassay CV (CV = 4.4%). Intact serum
PTH-(1–84) was measured using a solid phase, two-site chemiluminescent
immunometric assay (Immulite, Diagnostic Products Corp., Los Angeles,
CA). The intra- and interassay CVs were 4.7% and 5.0%, respectively.
The detection limit of the assay is approximately 0.1 pmol/liter.
Bone mineral analyses
At baseline and immediately before necropsy, piglets were
transported to the Department of Nuclear Medicine at McMaster
University under anesthesia, and whole body bone mineral content (BMC)
and bone mineral density (BMD) were measured using dual energy x-ray
absorptiometry (Hologic QDR1000W, Hologic, Waltham, MA) as previously
described (14). Whole body BMC and BMD were measured using the infant
whole body software program (V5.63P, Hologic). Piglets were placed on
the scan field on their abdomens with limbs extended from their bodies.
Repositioning CVs for the whole body scans were 1.2%.
Statistical analysis
One-way ANOVA or ANOVA with repeated measures was used to
determine whether significant differences existed among treatment
groups. The Student-Newman-Keuls test was used to compare multiple
means. Significant differences existed if P < 0.05.
All results were expressed as the mean ± SE, and
analyses were performed using SigmaStat software (Jandel Scientific,
San Rafael, CA).
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Results
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Anthropometry
There were no significant differences in weight or length among
the groups at the beginning of the experiment. Control and Tam alone
treated piglets were significantly heavier than Dex- plus Tam-treated
piglets on day 12; however, piglets treated with Dex plus Tam were
significantly heavier than Dex alone treated piglets. The rate of
weight gain is presented in Fig. 1
. The
change in length growth (snout to rump) over the 12-day study was
significantly (P < 0.01) less for Dex alone piglets
than for all other groups (control, 9.78 ± 1.1 cm; Dex, 5.16
± 0.68 cm; Dex plus Tam, 8.52 ± 0.82 cm; Tam, 9.66 ± 1.4
cm). Tam alone did not alter weight or length growth significantly
compared with those in placebo controls.
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Figure 1. Mean daily weights among treatment groups. The
mean rate of weight gain for each treatment group was calculated by
regression analysis of each piglet’s growth curve. The rates of weight
gain for Tam (59.1 ± 2.6 g/kg·day) and control (57.8 ±
2.3 g/kg·day) groups were significantly (P <
0.05) greater than those of the Dex plus Tam (46.4 ± 3.1
g/kg·day) and Dex alone (34.4 ± 0.8 g/kg·day) groups, whereas
the growth velocity for Dex- plus Tam-treated piglets was also
significantly (P < 0.05) greater than that for Dex
alone piglets. **, Significant difference in the rate of weight gain
compared with all other groups; *, significant differences in rate of
weight gain between the Dex plus Tam group and the Tam or Dex group
(P < 0.05). Data are expressed as the mean ±
SE.
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From a purely qualitative standpoint, it was observed that by day 12
the piglets treated with Dex alone had Cushingoid features and were
aggressive compared with the other groups. Dex alone treated piglets
were also consistently the first to consume their rations. Although Tam
was well tolerated, some loss of appetite in the Tam-treated group was
noted, but only over the first 3–4 days of treatment, after which
formula intake returned to control levels. In fact, the daily energy
intake did not differ significantly between groups at any time point
over the 12-day study (Table 1).
Biochemical analyses
Changes in plasma osteocalcin and PTH over the 12 days of
treatment were significantly greater in Dex alone treated animals
compared with all other groups (P < 0.05; Fig. 2). Urine volume, as an indication of
hydration status, was not significantly different among groups. Urinary
NTx concentration was significantly (P < 0.05) less
for Dex alone treated piglets than for all other groups on day 12 (Fig. 3). Dex alone treatment induced a 2-fold
suppression of NTx compared with the control value.
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Figure 2. Biochemical markers of bone turnover. A, Change in
plasma osteocalcin over 12 days. B, Change in PTH over 12 days. *,
Significant differences between Dex alone and all other groups
(P < 0.05). Data are expressed as the mean ±
SE.
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Figure 3. NTx expressed as bone collagen equivalents (BCE)
and corrected for creatinine. *, Significant differences between Dex
alone and all other groups (P < 0.05). Data are
expressed as the mean ± SE.
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Body composition and BMD
Significant reductions in whole body BMD and BMC were observed in
the Dex alone group compared with the control group (Fig. 4). These reductions were not observed in
the Dex plus Tam group for whole body BMD (Fig. 4). Lean and fat mass,
expressed as a percentage of body weight, did not significantly differ
among treatment groups (P = 0.345 and P
= 0.420, respectively; Table 2).
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Figure 4. The change in BMC (A) and BMD (B) over the 12-day
study. **, Significant difference from Tam or control groups; *,
significant difference between Dex alone and all other groups
(P < 0.05). Data are expressed as the mean ±
SE.
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Absolute organ weights were corrected for body weight to account for
the significant differences in body size between treatment groups at
necropsy. Liver and kidney weights were significantly higher in all
Dex-treated groups compared with controls, and Tam did not prevent this
change (Table 3). There were no
differences in heart or spleen weights among any of the groups (Table 3).
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Discussion
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To the best of our knowledge, this is the first study in which an
estrogen antagonist has been administered to prevent the
steroid-induced reduction of growth and bone mass in a rapidly
developing animal model. The impact of Dex alone on weight, length,
BMD, and the indirect biochemical markers of bone metabolism are
similar to previous findings (4, 13). These data indicate that Tam, a
sex steroid analog, has the capability to antagonize the actions of the
corticosteroid, Dex, in an in vivo model.
It has been postulated that Dex alters bone mineral homeostasis by
down-regulating intestinal calcium absorption and decreasing renal
calcium reabsorption (4). In this regard, piglets given Dex alone
experienced a secondary hyperparathyroidism, which is consistent with
the increase in PTH expected with decreased calcium absorption. In this
study, lower plasma osteocalcin and urinary NTx concentrations
suggested that Dex treatment suppressed both osteoblastic activity and
bone resorption, indicating an overall suppression of bone turnover
(6).
In vivo, Dex administration has deleterious effects on bone
(6, 13), whereas Tam has estrogen-like effects (15, 16, 17). In addition,
related findings in humans have suggested that Tam may inhibit
glucocorticoid induced-bone loss in postmenopausal females (1) and may
reduce the incidence of osteoporosis in postmenopausal females (18, 19). Thus, with respect to bone parameters, these two agents appear to
have opposite effects to each other both in vivo and
in vitro. Human studies on the effects of Tam on bone have
been mostly centered on women receiving Tam for breast cancer (17).
These studies suggest that Tam acts on bone as a partial estrogen
agonist (17). Tam studies on bone have largely focused on sexually
mature female intact or ovariectomized rodents (16, 20, 21, 22). One study
in male mice reported that Tam exposure was detrimental to femur and
pelvis calcium and phosphorus content (23). Generally, it appears that
any benefits realized through Tam therapy have occurred in an
estrogen-compromised state and, further, that the effects of Tam are
cell type dependent and in some cases species dependent (24).
As Tam alone treatment did not induce significant changes in any of the
parameters measured in the piglet model compared with those in
controls, one might conclude that Tam had no direct effects. Potential
mechanisms for Tam’s action on bone include antagonism of estrogen
receptor-dependent gene activation and direct estrogen receptor agonism
or up-regulation of transforming growth factor-ß production (15), but
it is not clear whether these mechanisms can be used to explain the
events that occurred in the animals used in the present study.
In contrast to our findings, administration of Tam in neonatal male
mice has been reported to inhibit postpubertal bone growth (23).
Similarly, Tam was shown to decrease body weight in both ovariectomized
and intact rats (20). We did not observe these reductions in weight and
bone growth with Tam in the piglet model. Perhaps the method of
administration, dosage, species-specific differences in drug handling
by the liver, or appetite suppression could be responsible for these
differences.
Similar to our in vivo study findings, in which Tam
abrogated the effects of glucocorticoid on bone, Tam was shown to
prevent bone loss in postmenopausal women receiving glucocorticoid
treatment (25). This is perhaps expected because studies using multiple
species have shown that Tam possesses inherent antiglucocorticoid
properties that are important in bone metabolism (10). Moreover, the
attenuation of Dex effects in ROS17/2.8 cells does not appear to be
related to inhibition of Dex uptake by target cells or through
inhibition of either estrogen or Dex binding to their cognate receptors
(10). Tam may abrogate Dex effects through posttranscriptional
modifications, which are as yet unclear. In this regard, previous
studies reported no down-regulation of Dex-mediated increases in
messenger RNA for various bone proteins despite reductions in the
respective proteins themselves (10). Further, on the basis of in
vitro data, it appears that Tam may have (receptor-independent)
pharmacological actions that are simply opposite those of Dex. Thus,
opposing pharmacological functions rather than direct inhibition by Tam
of the effects of Dex could be responsible for the decreased severity
of steroid actions.
Piglets receiving Dex with or without concurrent Tam treatment
experienced significant increases in liver and kidney weights,
suggesting that these increases were due primarily to the
corticosteroid treatment. Increases in relative liver size have also
been reported in several species pursuant to Dex treatment (26, 27).
Glucocorticoids decrease protein synthesis in muscle tissue and
increase hepatic free amino acids (28). The increased amino acid supply
to the liver has been shown to suppress protein degradation in the
liver as well as increase hepatic protein synthesis (28). This may
explain the increased liver size. In addition, Dex is known to
profoundly induce the cytochrome P450 3A subfamily in the liver and
kidney, and this may also contribute to the increase in weights of
these organs in Dex-treated piglets (29). Moreover, the oxidative
metabolism of Tam is mediated by cytochrome P450 3A, and studies in
rats demonstrate that Dex alters the metabolism of Tam, thereby
producing a metabolite potentially more active than the parent molecule
(29, 30). Thus, such an alteration could conceivably produce a
metabolite of Tam that could be involved in the down-regulation of Dex
effects.
We have demonstrated that adjunctive Tam therapy can improve growth and
favorably affect bone formation and other related parameters in
steroid-treated piglets. Notably, axial length, which was stunted
significantly with Dex administration, appears to be normalized with
concurrent Dex plus Tam administration. Treatment with Dex plus Tam
also maintained whole body BMD at control levels, indicating that the
bones of Dex-treated piglets are responsive to Tam. Functional tests
such as fracture resistance and other biomechanical tests are essential
to determine whether Dex alters these and whether such hypothetical
changes can be attenuated by Tam. These tests are now underway.
Given these findings, then, it is conceivable that Tam might be used to
attenuate the deleterious effects of Dex in humans. Clearly, as it has
not been established whether the desired therapeutic actions of Dex are
conserved with concurrent Tam administration, further studies need to
be performed. Nevertheless, these findings may point to some promising
applications of Tam in individuals undergoing chronic steroid
therapy.
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Acknowledgments
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The authors thank Nicole Campbell and Christopher McAllister for
their assistance with piglet care. We are also indebted to Drs. Jaro
Sodek and Christopher McCulloch for their valuable advice. We thank
Balram Sukhu for his assistance throughout this project.
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Footnotes
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1 This work was supported by a grant from the Faculty of Dentistry,
University of Toronto, and the Medical Research Council of Canada (to
H.C.T.). 
Received November 13, 1997.
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Abstract
Introduction
