The effect of different hormone replacement therapy regimens on the mechanical properties of rat vertebrae.
TL;DR: It is found that all three estrogen/progestin regimens maintain bone density and all mechanical properties at a level indistinguishable from the control, however, the cyclic and continuous NET treatment results were, with the exception of density, also indistinguishable from those of the ovariectomized group.
Abstract: The purpose of this study was to examine the effects of estrogen replacement, in concert with three different progestin regimens, on the mechanical properties of rat lumbar vertebrae. Ninety-two Sprague-Dawley rats (11 months old) were divided into six groups for treatment. The first group was an intact control, the second group (OVX) was ovariectomized only, and the third group (estrogen-only) was ovariectomized and received continuous estrogen through a 17 beta-estradiol implant. The remaining groups were ovariectomized and received estrogen and progestin (norethindrone, NET) therapy; 3 micrograms of NET was injected daily (estrogen plus continuous NET), or 6 micrograms of NET was injected for 14 consecutive days of a 28-day cycle (estrogen plus cyclic NET), or for 3 consecutive days of a 6-day cycle (estrogen plus interrupted NET). The animals were sacrificed after 6 months, and the vertebrae were dissected out. The vertebral processes of the fourth lumbar vertebrae were removed, and the density of the vertebral bodies was determined. They were then subjected to compression testing. We found that all three estrogen/progestin regimens maintain bone density and all mechanical properties at a level indistinguishable from the control. However, the cyclic and continuous NET treatment results were, with the exception of density, also indistinguishable from those of the ovariectomized group. The estrogen plus interrupted NET group on the other hand, has a significantly greater compressive modulus and density than the ovariectomized group. In conclusion, with respect to the ovariectomized group, the estrogen plus interrupted NET treatment resulted in a superior density and compressive modulus.(ABSTRACT TRUNCATED AT 250 WORDS)
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TL;DR: The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism, indicating an induction of functional progesterone receptors.
Abstract: In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17 beta-estradiol per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent, steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors. Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism.
402 citations
TL;DR: A highly sensitive three‐point bending test for the metaphyseal tibias in rats to evaluate stiffness and strength was developed and validated in a right‐left comparison and a bioassay with soy‐free food, estradiol, raloxifene, and testosterone in orchidectomized rats.
Abstract: The fracture of bone plays a key role in osteoporosis. BMD measurement, however, is only an indirect parameter of this phenomenon. We therefore developed a highly sensitive three-point bending test for the metaphyseal tibias in rats to evaluate stiffness and strength. This was validated in a right-left comparison and a bioassay with soy-free food, estradiol, raloxifene, and testosterone in orchidectomized rats. Introduction: Osteoporosis becomes manifest predominantly in the metaphyseal rat tibia. The anti-osteoporotic character of substances should, therefore, be tested (mechanically) in this bone area. Materials and Methods: We evaluated a new three-point bending test for the metaphyseal tibia in rats in a right-left trial. In an animal experiment, we studied the change of bone quality under estradiol (E)-, raloxifene (R)-, and testosterone (T)-supplemented food and compared it with trabecular BMD (qCT). Results: In the right-left comparison, the mean difference between the metaphyseal loads of both tibias in 37 rats was 8.43% for the maximum load (F m a x ) and 6.46% for the failure load (fL). These results show the high reproducibility of the test, because they are close to the usual intraindividual difference of the two extremities. In a second experiment, four groups of 11 3-month-old male orchidectomized rats were fed with soy-free food only (C) or with the additives E, T, or R for 12 weeks. E and R were similar for F m a x and fL. There were significant differences in the stiffness (E = 406.92 N/mm versus R = 332.08 N/mm), the yield load (yL; E = 99.17 N versus R = 83.33 N), and the ratio between yL and F m a x (E = 86.33% versus R = 76.37%). T was similar to the controls concerning F m a x , fL, and stiffness. There were significant differences in yL (T = 49.00N versus C = 39.5N) and the ratio between yL and F m a x (T = 64.28% versus C = 51.28%). Conclusions: Estradiol is superior to raloxifene concerning stiffness and yield load, and both are superior to testosterone. We conclude that the described three-point bending test for the metaphyseal tibia is a highly sensitive method to study hormones and substances with regard to their osteoprotective character. The precision and the low SD of the presented results are superior to the data from qCT and the calculated index of stiffness (SSI).
126 citations
TL;DR: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats, and these protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.
Abstract: Purpose: Exemestane (EXE) and letrozole (LET) are third-generation aromatase inhibitors currently prescribed for postmenopausal hormone-dependent breast cancer. The impact on end organs of estrogen depletion in menopausal women is of significant clinical importance. We studied the effects of EXE, its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone and lipid metabolism in ovariectomized (OVX) rats. Experimental Design: OVX rats were treated by weekly intramuscular injection for 16 weeks with 20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of 1 mg/kg LET. At the end of the treatment period, bone mineral density (BMD), the bone resorption marker serum pyridinoline, the bone formation marker serum osteocalcin, bone mechanical properties, histomorphometry, and serum lipid concentrations were determined. Results: Lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume were significantly higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE and 17-H-EXE significantly reduced an ovariectomy-induced increase in serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX rats caused significant reductions of serum cholesterol and low-density lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD, bone biomarkers, mechanical failure properties, and lipid levels similar to those of OVX controls. Conclusions: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats. These protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.
117 citations
Cites methods from "The effect of different hormone rep..."
...The body of the fifth lumbar vertebra was tested to failure in unconfined compression using a similar procedure described previously (14)....
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TL;DR: The positive results of EXE on bone and lipid metabolism in the OVX rat model merit further investigation of the effects of exemestane in postmenopausal women.
115 citations
Cites methods from "The effect of different hormone rep..."
...The body of the fifth lumbar vertebra was tested to failure in unconfined compression using a similar procedure previously described [18]....
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TL;DR: It is demonstrated that ERT can restore the lost trabecular bone, but not trabECular connectivity, that occurs soon after OVX by allowing bone formation to continue in previously activated bone remodeling units while suppressing the production of new remodelingunits.
Abstract: To evaluate the ability of estrogen replacement therapy (ERT) to prevent changes in trabecular bone volume (BV/TV) and connectivity beginning either at ovariectomy (OVX) or 5-13 days after OVX in adult female rats, the right proximal tibial was examined by three-dimensional X-ray tomographic microscopy (XTM) in vivo. Animals had XTM scans of the right tibia and then were randomized into six groups (n = 9). Groups 2-6 had bilateral (OVX), while group 1 was sham-ovariectomized (OVXd) on day 0. Animals were treated with vehicle (groups 1 and 2) or 17beta-estradiol therapy (ERT) at 10 microg/kg three times per week starting at days 0, 5, 8, and 13 post-OVX (groups 3, 4, 5, and 6), until day 50 when they were rescanned by XTM and sacrificed. Trabecular bone structural variables were calculated from XTM data (BV/TVx and beta1/BV/TVx) and standard histomorphometry. Trabecular bone volume (BV/TVx) and the trabecular connections per cubic millimeter of trabecular bone (beta1/BV/TVx) were maintained in both sham-OVXd animals and OVX animals given ERT from the time of OVX. However, OVX + vehicle-treated animals lost 54% BV/TVx and 46% beta1/BV/TVx (p < 0. 01 from day 0). BV/TVx and beta1/BV/TVx decreased rapidly post-OVX to -22% and -25% at day 13 (p < 0.01 from day 0). ERT initiated at day 5, 8, and 13 post-OVX restored BV/TVx to baseline values at day 50 by modestly increasing trabecular plate thickness; however, beta1/BV/TVx was reduced in all OVX groups when compared with their baseline values. ERT also caused a significant reduction in bone turnover compared with OVX + vehicle; however, resorption was suppressed more than formation. These results demonstrate that ERT can restore the lost trabecular bone, but not trabecular connectivity, that occurs soon after OVX by allowing bone formation to continue in previously activated bone remodeling units while suppressing the production of new remodeling units. This may be the mechanism by which prompt intervention with estrogen and other antiresorptive agents can restore bone mass that has been lost from the increase in remodeling space, and thereby reduce the risk of osteoporotic fractures in postmenopausal women.
100 citations
References
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TL;DR: Ovariectomy induced bone loss in the rat and postmenopausal bone loss share many similar characteristics, including: increased rate of bone turnover with resorption exceeding formation; and initial rapid phase of bone loss followed by a much slower phase.
1,329 citations
"The effect of different hormone rep..." refers background in this paper
...Grynpas, Samuel Lunenfeld Research Institute bone quality increase the risk of fractures [5-7]....
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TL;DR: The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism, indicating an induction of functional progesterone receptors.
Abstract: In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17 beta-estradiol per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent, steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors. Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism.
1,156 citations
"The effect of different hormone rep..." refers background in this paper
...Recent studies have revealed high affinity nuclear binding sites for 1713-estradiol in human osteoblast-like cells [ 8 ], and in true osteoblasts [9]....
[...]
TL;DR: Estradiol can act directly on osteoblasts by a receptor-mediated mechanism and thereby modulate the extracellular matrix and other proteins involved in the maintenance of skeletal mineralization and remodeling.
Abstract: High specific activity estradiol labeled with iodine-125 was used to detect approximately 200 saturable, high-affinity (dissociation constant approximately equal to 1.0 nM) nuclear binding sites in rat (ROS 17/2.8) and human (HOS TE85) clonal osteoblast-like osteosarcoma cells. Of the steroids tested, only testosterone exhibited significant cross-reactivity with estrogen binding. RNA blot analysis with a complementary DNA probe to the human estrogen receptor revealed putative receptor transcripts of 6 to 6.2 kilobases in both rat and human osteosarcoma cells. Type I procollagen and transforming growth factor-beta messenger RNA levels were enhanced in cultured human osteoblast-like cells treated with 1 nM estradiol. Thus, estrogen can act directly on osteoblasts by a receptor-mediated mechanism and thereby modulate the extracellular matrix and other proteins involved in the maintenance of skeletal mineralization and remodeling.
811 citations
"The effect of different hormone rep..." refers background in this paper
...An estrogen receptor was also found in rat osteoblast and osteosarcoma cells in culture [10], and mRNA for estrogen receptors has been detected in osteoclasts [11]....
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TL;DR: Because of the aging of the population and increases over time in the incidence of fractures, these already huge costs will more than double over the next 30 years unless a comprehensive program of prevention and treatment is initiated soon.
Abstract: OSTEOPOROSIS is one of the most important disorders associated with aging.1 , 2 More than 1.5 million Americans have fractures related to osteoporosis each year, with attendant pain, deformity, and loss of independence. The annual cost to the U.S. health care system is at least $10 billion.1 , 2 Because of the aging of the population and increases over time in the incidence of fractures, these already huge costs will more than double over the next 30 years3 unless a comprehensive program of prevention and treatment is initiated soon. The most important preventable cause of fractures is low bone mass. During the course of . . .
716 citations
TL;DR: The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism, indicating an induction of functional progesterone receptors.
Abstract: In seven strains of cultured normal human osteoblast-like cells, a mean of 1615 molecules of tritium-labeled 17 beta-estradiol per cell nucleus could be bound to specific nuclear sites. The nuclear binding of the labeled steroid was temperature-dependent, steroid-specific, saturable, and cell type-specific. These are characteristics of biologically active estrogen receptors. Pretreatment with 10 nanomolar estradiol in vitro increased the specific nuclear binding of progesterone in four of six cell strains, indicating an induction of functional progesterone receptors. RNA blot analysis demonstrated the presence of messenger RNA for the human estrogen receptor. The data suggest that estrogen acts directly on human bone cells through a classical estrogen receptor-mediated mechanism.
402 citations
"The effect of different hormone rep..." refers background in this paper
...Recent studies have revealed high affinity nuclear binding sites for 1713-estradiol in human osteoblast-like cells [8], and in true osteoblasts [9]....
[...]