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Endocrinology Vol. 144, No. 4 1481-1485
Copyright © 2003 by The Endocrine Society

ARTICLE

Raloxifene Acts as an Estrogen Agonist on the Rabbit Growth Plate

Ola Nilsson, Jens Falk, E. Martin Ritzén, Jeffrey Baron and Lars Sävendahl

Pediatric Endocrinology Unit (O.N., J.F., E.M.R., L.S.), Department of Women and Child Health, Karolinska Institutet, SE-17176 Stockholm, Sweden; and Developmental Endocrinology Branch (O.N., J.B.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ola Nilsson, National Institutes of Health, National Institute of Child Health and Human Development, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: ola.nilsson{at}kbh.ki.se.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Estrogen treatment has been used to induce growth plate fusion, thereby reducing the final height in girls expected to achieve extreme tall stature. The treatment is effective, in terms of limiting final height, but concerns have been raised that it might also increase the risk for malignancies later in life. Raloxifene, a selective estrogen receptor modulator, has been shown to act as an estrogen agonist on bone density but as an estrogen antagonist on breast and uterine tissue. The effect of raloxifene treatment on growth plate fusion and final height is unknown. The aim of this study was to determine whether raloxifene would act as an estrogen agonist or antagonist on growth plate cartilage. Ovariectomized immature rabbits were treated for 4 wk with vehicle (controls), estradiol cypionate (E2), or raloxifene. Tibial growth velocity was decreased in both E2- (P < 0.001) and raloxifene-treated animals (P < 0.001), compared with controls. E2 and raloxifene treatment also decreased chondrocyte proliferation and the height of the proximal tibial growth plate. In addition, E2 and raloxifene hastened fusion of the distal tibial growth plate (P < 0.05) and decreased the number of proliferative and hypertrophic chondrocytes per column in the proximal tibial growth plate. As expected, the uterus was enlarged by estrogen, but not raloxifene, treatment. We conclude that raloxifene acts as an estrogen agonist on the growth plate, accelerating growth plate senescence and thus hastening epiphyseal fusion.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE RATE OF longitudinal bone growth decreases with increasing age. This decrease is caused by a decline in chondrocyte proliferation, matrix production, and terminal hypertrophic cell height (1, 2). There is also a gradual decline in the overall growth plate height, proliferative zone height, hypertrophic zone height, size of hypertrophic chondrocytes, and column density (3, 4, 5). As a final step, the senescent growth plate is replaced by bone, a process termed epiphyseal fusion.

Estrogen advances this senescence program, thus hastening epiphyseal fusion (6). This effect has been exploited clinically; estrogen therapy has been used to reduce final height in girls predicted to reach an unusually tall stature (7, 8).

Selective estrogen receptor modulators (SERMs), which, to date, have been used primarily for the treatment of breast cancer and postmenopausal osteoporosis, have the potential to serve as clinical tools to modulate pubertal growth. Tamoxifen, a SERM that acts as an estrogen antagonist in breast and bone, seems to act as an estrogen antagonist at the growth plate, slowing skeletal maturation in patients with precocious puberty attributable to McCune-Albright syndrome (9). Raloxifene, a second-generation SERM, acts as an estrogen agonist on bone density and as an estrogen antagonist in breast and uterine tissue (10). In rats, raloxifene has been shown to inhibit longitudinal bone elongation (11). However, rats do not undergo epiphyseal fusion and may therefore not be the appropriate model for studies of human growth. The effect of raloxifene treatment on growth plate senescence, epiphyseal fusion, and final height is unknown. We hypothesized that raloxifene would act as an estrogen agonist on the growth plate and thereby has the potential to reduce final height. Using a well-characterized rabbit model, ovariectomized rabbits were given vehicle, raloxifene, or estradiol cypionate (E2) to determine the effects on growth rate, growth plate structure, and epiphyseal fusion.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Fifteen New Zealand White female rabbits (ESF Produkter I Estuna, Norrtälje, Sweden) were ovariectomized at the age of 12 wk. All animals were housed in an approved animal facility with a 12-h light cycle and fed a standard rabbit chow (78 g twice a day; K5, Brogaarden, Gentofte, Denmark) and water ad libitum. The protocol was approved by the Northern Stockholm Animal Ethics Committee.

Study design
The animals were randomized into three groups (five animals/group) and received E2, raloxifene, or vehicle (controls) for 4 wk, starting at the age of 16 wk. E2 (70 µg/kg) or vehicle (sesame oil) was administered as a weekly im injection. Raloxifene (210 mg/d) was delivered in specially prepared rabbit chow (Brogaarden). The estrogen and control groups received the same chow without raloxifene added. Blood was drawn from three animals in each group, 2 d after the second injection and immediately before the third injection, for measurement of E2, estrone, and IGF-1. The growth rate was determined by measuring the length of tibiae on radiographs obtained at the start of treatment and after 4 wk. For the radiographs, animals were sedated with im Hypnorm, 0.1 ml/kg (0.2 mg fentanyl and 10 mg fluanizon/ml; Janssen Pharmaceuticals-Cilag Pharmaceuphtical, Beerse, Belgium) and positioned together with a length standard on a horizontal cassette containing a digital imaging plate (Fuji Photo Film Co., Ltd. (Europe) GmbH, Düsseldorf, Germany). The plate was scanned and converted into a digital picture in an AC-3 Image plate reader (Fuji Photo Film Co., Ltd.). The maximal length of each tibia was measured using a Sectra IDS4/clinic workstation (Sectra Imtec AB, Linköping, Sweden). All animals were killed 4 wk (±2 d) after the start of treatment. The animals were given an ip injection of BrdU (50 mg/kg; Sigma, St. Louis, MO), 7 h and 2 h before killing. Tibiae were processed for histological analysis, and the uterine weights were measured.

Proliferation index
BrdU is incorporated into DNA during replication, and thus the number of BrdU-labeled cells per column reflects the number of proliferating cells per column.

BrdU-labeled cells were visualized in the proximal tibial growth plate by immunohistochemical staining for BrdU, using a BrdU staining kit (catalog no. HCS24; Oncogene Science, Inc., Cambridge, MA) according to the manufacturer’s protocol, except that antigen unmasking was performed in 0.01 M citrate buffer (pH 6.0) at 94–98 C. The number of labeled cells per column was counted in 10 proliferative columns for each animal.

Quantitative histology
Histological parameters were assessed on Masson Trichrome-stained sections of proximal tibial growth plates, using a light microscope with a VIA-100 video measurement system (Boeckeler, Tucson, AZ). All histological measurements were performed in the central two thirds of the growth plate sections, by an observer blinded to treatment group. For growth plate height and column density, measurements from four different areas of each growth plate were averaged. The number of proliferative and hypertrophic cells were counted in 20 columns per growth plate and averaged for each growth plate. The hypertrophic chondrocytes were defined by a height more than 10 µm. The height of the terminal hypertrophic chondrocyte, the cell in the last intact lacuna, was measured in 25 different columns per growth plate and averaged. Sections of the distal tibia were evaluated for growth plate fusion by a blinded observer, as previously described (12). Areas with chondrocytes arranged in columns were considered unfused (Fig. 1AGo), whereas areas where columns were replaced by blood vessels and bone cells were considered to be fused (Fig. 1Go, B and C). The percent fusion was estimated visually, and growth plates were considered to be fused if 50% or more of the total length was fused.



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  		Figure 1. Effect of raloxifene and estrogen treatment on distal tibial epiphyseal fusion and uterine growth. Ovariectomized rabbits were treated with either vehicle (A), im E2 (B), or oral raloxifene (C) for 4 wk. Representative microphotographs showing sagittal, Masson Trichrome-stained sections of the distal tibial growth plate. Representative photographs of uteri from vehicle- (D), E2- (E), and raloxifene- (F) treated animals.

 
Hormone assays
Plasma levels of estrogens (E1 and E2) and IGF-1 were determined at Esoterix (Calabasas Hills, CA), by HPLC and RIA, respectively.

Statistics
Data are expressed as mean ± SEM. The effects of the different treatments were evaluated using a one-way ANOVA test, followed by a Bonferroni t test for pair-wise comparison. A Kruskal-Wallis one-way ANOVA on Ranks test was used to evaluate the effects on epiphyseal fusion. For pair-wise comparison, a Wilcoxon rank-sum test, followed by an adjustment for multiplicity according to the method of Holm, with logical constraints, was used.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Body weight gain and uterine weight
Body weights were similar in all groups at the start of treatment (data not shown). Neither E2 nor raloxifene treatment affected body weight gain (Table 1Go). E2 treatment increased the uterine weight, compared with control animals (P < 0.001), whereas raloxifene did not significantly affect the uterine weight (Table 1Go).


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  		Table 1. Body weight gain, uterine weight, and serum IGF-1 (mean ± SEM)

 
Growth rate and epiphyseal fusion
Tibial length was similar in all groups at the start of treatment (95.6 ± 2.9 vs. 96.2 ± 2.8 vs. 96.3 ± 2.5 mm; control vs. estradiol vs. raloxifene, respectively). Treatment with E2 (P < 0.001) and raloxifene (P < 0.001) decreased the tibial growth rate (Fig. 2AGo). Both E2 and raloxifene also advanced epiphyseal fusion. At the end of treatment, the distal tibial growth plates were fused in three of five (P < 0.05 vs. control) in the E2- and four of five animals (P < 0.05 vs. control) in the raloxifene-treated groups (Figs. 1Go, B and C, and 2CGo). In contrast, none of the control animals had fused their distal tibial growth plate (Figs. 1AGo and 2CGo). Because of the different timing of epiphyseal fusion between different growth plates, the growth plates of distal femur and proximal tibia were still open in all animals at the end of the treatment period.



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  		Figure 2. Effect of estrogen and raloxifene treatment on tibial growth rate, growth plate chondrocyte proliferation, and epiphyseal fusion. Ovariectomized rabbits were treated with either vehicle, im E2, or oral raloxifene for 4 wk. A, Tibial length was determined from radiographs obtained at the start and at the end of treatment. B, Proliferating chondrocytes were detected by BrdU immunohistochemistry in the proximal tibial growth plate. The number of BrdU-positive cells/total number of cells were calculated in 10 columns per animal and averaged. C, The percent fusion was estimated visually on sagittal, Masson Trichrome-stained sections of the distal tibial epiphysis. *, P < 0.05; **, P < 0.001 vs. vehicle (ANOVA).

 
Chondrocyte proliferation and quantitative histology at the proximal tibial growth plate
Treatment with raloxifene, like E2 treatment, decreased the number of proliferating cells per column, as assessed by BrdU labeling in proximal tibial growth plates, by approximately 50% (P < 0.05; Fig. 2BGo). As is seen for E2 treatment, raloxifene also advanced the morphological characteristics associated with senescence of the growth plate. Compared with controls, both E2 and raloxifene significantly decreased the growth plate height (Fig. 3AGo), the number of proliferative (Fig. 3BGo) and hypertrophic cells per column (Fig. 3CGo), column density (Fig. 3DGo), and the terminal hypertrophic cell height (Fig. 3EGo).



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  		Figure 3. Effect of estrogen and raloxifene treatment on growth plate structure. Ovariectomized rabbits were treated with either vehicle, im E2, or oral raloxifene for 4 wk. For quantitative histology, a video measuring system was used, and measurements were performed on sagittal, Masson Trichrome-stained sections of the proximal tibial growth plate. C, Hypertrophic chondrocytes were defined by size (>10 µm). The terminal hypertrophic chondrocyte was defined as the chondrocyte in the last intact lacuna of each column. *, P < 0.05; **, P < 0.001 vs. vehicle (ANOVA).

 
Serum hormone levels
In the E2-treated group, the plasma E2 levels varied from 123 ± 3 pg/ml (to convert to picomoles/liter, multiply by 3.671) at peak (2 d after the second injection) through 19 ± 2 pg/ml (before the third injection), whereas both the controls and the raloxifene-treated groups had plasma E2 levels below the detection limit of the assay (<5 pg/ml). The E1 levels were similar for the controls (24 ± 3 pg/ml; to convert to picomoles/liter, multiply by 3.699), the E2- (39 ± 6 pg/ml), and the raloxifene- (24 ± 3 pg/ml) treated groups. Neither were there any significant differences in serum IGF-1 between the controls, the E2-, or the raloxifene-treated animals (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Raloxifene had estrogen-like effects on the growth plates of ovariectomized rabbits. Like E2, raloxifene inhibited growth plate function, decreasing the rate of growth plate chondrocyte proliferation and the rate of longitudinal bone growth. Raloxifene also had estrogen-like effects on growth plate structure, decreasing growth plate height, number of proliferative and hypertrophic cells per column, and terminal hypertrophic cell height. Like estrogen, raloxifene also hastened epiphyseal fusion. Although animals were not followed to the end of growth in this study, it is likely that raloxifene, like estrogen, would decrease final skeletal size because they both decreased growth rate and also hastened fusion, both of which effects would tend to diminish adult skeletal dimensions.

The functional and structural changes induced by raloxifene treatment also occur during normal aging (4). Some of these growth plate effects (6), such as decreased heights of the total growth plate, the proliferative zone, and the hypertrophic zone, are induced by other growth-inhibiting conditions, such as glucocorticoid excess (12), hypophysectomy (13), or fasting (14). However, the combination of a decreased growth rate and advanced growth plate senescence and fusion, without qualitative changes to the growth plate, seems to be an effect specific to estrogen treatment (15).

The various effects of raloxifene on growth plate function and structure are probably not independent but rather are probably interrelated. For example, the observed deceleration in longitudinal bone growth induced by estrogen and raloxifene can be explained by the decreased rate of chondrocyte proliferation and the decreased height of the terminal hypertrophic chondrocyte (16, 17). Similarly, the decreased growth plate height and the decreased number of proliferative and hypertrophic chondrocytes per column may be a consequence of the decreased chondrocyte proliferation in the proliferative zone.

Raloxifene did not significantly affect the body weight gain or the serum levels of IGF-1. The observed effects of raloxifene on the growth plate are therefore unlikely to be mediated by indirect, systemic alterations in nutritional status or in the somatotrophic axis. Instead, raloxifene and estrogen may act directly on the growth plate through estrogen receptor-{alpha} and -ß, both of which are expressed by growth plate chondrocytes (18, 19). For example, the decrease in chondrocyte proliferation might be mediated directly through estrogen receptors expressed in the proliferative zone (18, 20) or, as suggested by Weise et al. (6), indirectly via an effect on the senescence of the stem-like cells located in the resting zone (21), or by a combination of these effects. The decrease in terminal hypertrophic cell height indicates an effect on chondrocyte differentiation. Likewise, this effect could be mediated directly through estrogen receptors expressed in the hypertrophic cells (20, 22) and/or indirectly via effects on the senescence of the stem-like resting chondrocytes (6).

We selected a model system that, in some ways, simulates human estrogen and raloxifene treatment. We performed the study in rabbits because estrogen advances growth plate senescence and hastens epiphyseal fusion in rabbits (6), as it does in humans. This effect on fusion is not seen in rodents. We also used an E2 regimen, which was previously shown to produce near-physiological serum concentrations (6). Similarly, raloxifene was administered in a regimen shown to produce plasma raloxifene levels comparable with those of postmenopausal women during raloxifene treatment (23). In rabbits, as in humans, raloxifene did not stimulate uterine growth.

Our findings raise the possibility that raloxifene and other SERMs could be used clinically to accelerate growth plate senescence, hasten epiphyseal fusion, and thus decrease adult height. Previously, estrogen has been used for this purpose, particularly for girls predicted to reach an unusually tall stature. This clinical application for estrogen therapy is controversial, in part because of the question of long-term risks (24). New SERMs with less adverse effects on liver, breast, and uterus have the potential to be valuable tools for the manipulation of pubertal growth. Theoretically, a SERM could act as an estrogen antagonist on the growth plate and as an agonist on pituitary GH-secretion and thereby be used to increase final height. Conversely, a SERM that advances growth plate senescence and inhibits the somatotrophic axis could be used to reduce final height. Our data indicate that raloxifene advances growth plate senescence and may therefore provide an alternative to estrogen for the treatment of girls with expected extreme tall stature. However, raloxifene treatment has been correlated with an increased incidence of venous thrombosis (25) and may therefore not be the ideal SERM for this purpose.

In summary, we conclude that raloxifene acts as an estrogen agonist on the growth plate, accelerating growth plate senescence, thus hastening epiphyseal fusion. Our findings suggest that SERMs might provide an alternative clinical treatment to induce growth plate fusion, while avoiding possible risks associated with estrogen action on the breast and endometrium.


   Acknowledgments
 
We thank Ann Hagström and Jenny Lindberg at the Department for Physiology and Pharmacology, Karolinska Institutet (Stockholm, Sweden) for technical support.


   Footnotes
 
This work was supported by the Swedish Medical Research Council (K00-72X-13508-01A), HKH Kronprinsessan Lovisas förening för Barnasjukvård, Lennanders Stiftelse, Stiftelsen Sven Jerrings Fond, Stiftelsen Samariten, Sällskapet Barnavård, Wera Ekströms Stiftelse, Stiftelsen Frimurare Barnhuset i Stockholm, and Emil och Wera Cornells Stiftelse.

Abbreviations: E2, Estradiol cypionate; SERM, selective estrogen receptor modulator.

Received October 25, 2002.

Accepted for publication December 18, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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