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Pfizer Global Research and Development, Groton Laboratories (H.Z.K., H.A.S., D.D.T.), Groton, Connecticut 06340; Pfizer Global Research and Development, Ann Arbor Laboratories (G.L.F.), Ann Arbor, Michigan 48105; and Skeletech, Inc. (V.S.), Bothell, Washington 98021
Address all correspondence and requests for reprints to: Dr. H. Z. Ke, Osteoporosis Research, Mail Stop 8118W-216, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340. E-mail: huazhu_ke{at}groton.pfizer.com.
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Introduction |
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Estrogen or estrogen plus progestin [hormone replacement therapy (HRT)] is effective in preventing the bone loss and reducing the incidence of bone fractures in postmenopausal women (3, 4, 5, 6). Further, HRT is efficacious in the treatment of menopausal symptoms and is considered the standard of care in alleviating hot flashes in postmenopausal women in whom therapy is generally given over a relatively short period of time (7). However, large scale randomized clinical trials (the Women’s Health Initiatives) have demonstrated that significant adverse events, including increased coronary heart disease, strokes, pulmonary embolism, and invasive breast cancer, occur more commonly in women receiving HRT (conjugated equine estrogen and medpoxyprogesterone acetate) than in women receiving placebo (6). In the same trial, Hayes and colleagues (8) found that HRT did not have a clinically meaningful effect on health-related quality of life. Despite beneficial effects on osteoporosis and postmenopausal symptoms, adverse events limit the long-term use of HRT (9). Thus, there is a great medical need for new therapies without the concerns raised by HRT.
Emerging therapies offer potential benefits over HRT for postmenopausal women provided that they can maintain the positive effects of estrogen on the skeleton while minimizing the adverse events and carcinogenic potential of estrogen. Selective estrogen receptor modulators (SERMs) offer such therapeutic potential (10). Raloxifene, a second generation SERM originally studied for its use as a treatment for breast cancer when tamoxifen failed, has demonstrated bone protective effects, a reduction in skeletal fracture incidence in postmenopausal women, and a reduction in breast cancer incidence (11, 12, 13). Lasofoxifene, a new SERM developed for its bone and lipid effects (14), is currently under clinical investigation for the prevention and treatment of osteoporosis in postmenopausal women. In a short-term (4 wk) preclinical study, lasofoxifene was demonstrated to prevent bone loss and decrease serum cholesterol in ovariectomized (OVX) rats without producing significant uterine hypertrophy (14). Lasofoxifene has also been shown to prevent bone loss induced by aging or orchidectomy in male models of osteoporosis without significant effects on the prostate (15, 16). Further, Cohen and colleagues (17) found that lasofoxifene possessed chemopreventive and therapeutic activity in the N-methylurea-induced rat mammary tumor model. The results from the most recent, 1-yr clinical trial indicated that lasofoxifene significantly decreased low density lipoprotein cholesterol and biochemical markers of bone turnover and significantly increased lumbar spine bone mineral density (BMD) in postmenopausal women (18).
To be effective, osteoporosis therapy must maintain efficacy and safety over an extended period of time to reflect clinical practice, enabling postmenopausal women to maintain therapy for more than 30 yr. Although the bone efficacy and uterine safety of lasofoxifene have been demonstrated in OVX rats in short-term (4 wk) studies, long-term effects of lasofoxifene (such as those seen at 52 wk) on bone and uterine tissue in OVX rats have not been previously reported. In this study we investigated the effects of long-term (52 wk) treatment with lasofoxifene in the OVX rat model to determine lasofoxifene’s long-term efficacy in bone protection and long-term safety in uterine tissue. Because significant bone loss is observed in the lumbar spine, femur, and tibia after OVX in the rat (19, 20, 21), this is a well accepted animal model to assess the long-term efficacy of an antiosteoporosis compound such as lasofoxifene (22).
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Materials and Methods |
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Twenty-five rats were sham-operated (sham controls) and treated with vehicle (0.5% methylcellulose; 1 ml/rat·d, oral gavage), and 100 rats were bilaterally OVX and treated with lasofoxifene [0 (vehicle, OVX controls), 60, 150, or 300 µg/kg body weight·d, by oral gavage, at the dosing volume of 1 ml/rat] for 52 wk. There were 25 rats in each group.
All rats were given ip injections (10 mg/kg) of calcein green (Sigma-Aldrich Corp., St. Louis, MO), a fluorochrome bone marker, before necropsy to determine dynamic changes in bone tissue. As the rats were 15.5 months old and expected to have lower bone turnover, four calcein injections were given on d 14, 13, 4, and 3 before necropsy. Rats were necropsied under anesthesia and were euthanized by CO2 asphyxiation.
Animal health and body weight
Rats were observed daily, before each daily dosing, for signs of ill health or reaction to treatment. In addition, a more thorough observation, including palpation for masses, was performed once a week. Any change, appearance, or disappearance of clinical signs was recorded in the study record. Body weights were taken once every 2 wk immediately before and during the treatment period.
Serum osteocalcin and urinary deoxypyridinoline/creatinine ratio
Blood (1.5 ml) for bone turnover marker determinations was collected from the retroorbital sinus after a 6-h fast at wk 26 while the rats were under ether anesthesia. At wk 52, the samples were collected from the rats under ether anesthesia, approximately 1 wk before necropsy. The blood was allowed to clot at room temperature, and the serum was separated by centrifuging at 1015 x g for 10 min at approximately 4 C. The serum samples were stored frozen (approximately -70 C) until analysis. Serum osteocalcin was assayed using a rat osteocalcin immunoradiometric assay kit (Immutopics, Inc., San Clemente, CA).
Urine samples were collected for approximately 18 h at 26 and 52 wk of treatment. Urine was collected using metabolic cages. Animals were provided food and water during the collection period. The urine was then centrifuged at approximately 1015 x g for 5–10 min at approximately 4 C to remove contaminating sediments and divided into tubes. Aliquots were stored frozen at approximately -70 C until analyzed for deoxypyridinoline and creatinine. Urinary deoxypyridinoline was assayed using a Metra DPD ELISA kit (Quidel Corp., San Diego, CA). Urinary creatinine was measured using a COBAS automated analyzer and creatinine reagent (Roche, Indianapolis, IN). The data were expressed as a ratio of urinary deoxypyridinoline (nanomolar concentrations)/creatinine (millimolar concentrations).
Ex vivo peripheral quantitative computed tomography (pQCT)
A pQCT scan was performed on the left tibia using a Stratec XCT-RM and associated software (software version 5.40, Stratec Medizintechnik Gmbh, Pforzheim, Germany). The metaphyseal region of the left proximal tibia was scanned at a site that is 12.5% of the total length from the proximal articular surface. The position was verified using scout views, and one 0.5-mm slice perpendicular to the long axis of the tibia shaft was recorded. The scans were analyzed using a threshold for delineation of the external boundary and an area peel for subdivision into cortical and trabecular regions. Trabecular bone content and density were determined (16).
Trabecular bone histomorphometry
Undecalcified, methyl-methacrylate-embedded, sagittal sections of fifth lumbar vertebral bodies (LVB; LV5) and longitudinal sections of proximal tibial metaphysis (PTM) at 4- and 10-µm thickness were prepared for histomorphometry as described previously (14, 15, 16). One 4-µm section for each rat was stained with Goldner’s Trichrome stain for static histomorphometry. Another 4-µm section for each rat was stained with toluidine blue for measurements of osteoid surface and osteoid width, and a 10-µm section was left unstained for dynamic histomorphometry (23). Bone histomorphometry was performed using an OsteoMeasure Image Analysis System (software version 2.2, Osteometrics, Inc., Atlanta, GA) connected via a video system to a suitable light/epifluorescent microscope in a blind fashion. For PTM, the measurement site was an area between 0.5–2.9 mm distal to the growth plate epiphyseal junction and 0.5 mm away from the endocortical surface on either side. For LV5, the measurement site corresponded to an area approximately 4 mm2 within the central portion of the vertebral body. The indices of bone mass and structures (trabecular bone volume, thickness, number, and separation), bone resorption (osteoclast number per millimeter trabecular surface and percentage of osteoclast surface/trabecular surface), and bone formation and turnover (osteoid surface, osteoid width, mineralizing surface, mineral apposition rate, and bone formation rate/bone surface referent) were determined as described previously (24, 25).
Mechanical testing of the fourth LVB (LV4)
Biomechanical testing of LV4 was performed using an Instron 5500 servo-electric testing machine and associated Merlin II software (version 4.05, Instron, Canton, MA). Before testing, any remaining soft tissue was removed from the bones. Spinous and transverse processes were removed from each lumbar vertebra using a low speed diamond wheel saw. In addition, the ends of each vertebra were trimmed to provide two parallel surfaces for biomechanical testing. The 4-mm segment prepared from the center of the vertebral body was used in the testing. Before testing, the bones were thawed in cold saline and were not allowed to dry. The load was applied at 6 mm/min for all tests.
The cross-sectional area of each vertebral body was determined (area = 
x medial lateral width x anterior posterior width/4). The height of the vertebral body tested was recorded. The vertebral body segment was placed on a compression jig and compressed until failure at a displacement rate of 6 mm/min using a 5000 N load cell. The extrinsic parameters [maximum load to failure, stiffness (slope of the load displacement curve), and energy to failure (the area under the load displacement curve)] and intrinsic parameters (ultimate strength, elastic modulus, and toughness) were determined (15).
Reproductive tissues
At necropsy, a gross examination of the reproductive tract was conducted. Uterine wet weight was determined for all study animals. Reproductive tissues collected from all animals included uterus, cervix/vagina, and mammary gland tissue. All tissues were immersion-fixed in 10% neutral buffered formalin. After fixation, uterine and cervix/vagina tissues were trimmed. Uterine sections consisted of a transverse section of each uterine horn, collected at approximately midhorn, and a longitudinal section of uterine horns and body. All trimmed specimens (uteri, cervix/vagina, and mammary glands) were processed into paraffin blocks, sectioned at 4–8 µm, placed on glass microscope slides, and stained with hematoxylin and eosin. All tissues were examined microscopically for all animals in a nonblinded fashion.
Statistics
Descriptive statistics include mean, SD, and median for each of the parameters measured at each time point. Data (untransformed) were analyzed for normality (Shapiro-Wilke test) based on treatment groups. If the data were normally distributed, a two-tailed t test was performed to compare the sham group with the OVX/vehicle group. A one-way (dose) ANOVA was performed to ascertain the treatment effect difference between OVX vehicle and the three different doses of lasofoxifene groups at an 
= 0.05 level. If there was an overall difference, then Dunnett’s procedure was used to determine the individual group differences at = 0.05. If the data were not normally distributed, a nonparametric Wilcoxon rank-sum test was performed to determine intergroup differences, if any. All statistical analyses were performed using SAS statistical software (version 6.0, SAS Institute, Inc., Cary, NC).
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Results |
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Despite pair-feeding, the OVX controls gained approximately 10–15% more weight than the sham controls over the 52 wk of the study (Fig. 1
). Compared with sham controls, body weight in OVX controls significantly increased beginning at wk 3 and continued to be significantly higher throughout the study. Treatment with lasofoxifene at all doses similarly prevented the OVX-related weight gain (Fig. 1). Body weight in OVX rats treated with lasofoxifene at 300 µg/kg·d was significantly lower than that in sham controls beginning at wk 3 and continued to be lower throughout the study. Similarly, body weights in OVX rats treated with lasofoxifene at 100 and 60 µg/kg·d were significantly lower than those in sham controls beginning at wk 7 and 9, respectively, and were lower throughout the study. The observed weight loss after lasofoxifene treatment was possibly due to the reduction in fat body mass associated with lasofoxifene treatment, as observed in the short-term studies with female and male rats (14, 16). Sham control rats ate, on the average, 13–17 g food/d. The slight decrease in weight at approximately 26 wk was due to anesthetization for a 26-wk blood sample (Fig. 1).
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). Compared with OVX controls, treatment of OVX rats with lasofoxifene resulted in 14% (P < 0.01), 8% (P > 0.05), and 4% (P > 0.05) reductions in serum osteocalcin in the 60, 150, and 300 µg/kg·d dose groups, respectively. Urinary deoxypyridinoline/creatinine significantly reduced (P < 0.001) by 27%, 31%, and 33% in the 60, 150, and 300 µg/kg·d groups of lasofoxifene-treated OVX rats, respectively, compared with OVX controls (Fig. 2)
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). However, compared with the values at wk 26, OVX controls showed a 42% decrease in both serum osteocalcin and urinary deoxypyridinoline/creatinine levels at wk 52. Treatment of OVX rats with lasofoxifene resulted in a nonsignificant reduction in serum osteocalcin in the 60 and 150 µg/kg·d groups compared with OVX controls, whereas at 300 µg/kg·d, there was a statistically significant increase in serum osteocalcin of 12% in lasofoxifene-treated rats compared with OVX controls (Fig. 2A). Urinary deoxypyridinoline/creatinine did not significantly differ among OVX controls and OVX rats treated with lasofoxifene at 60 and 150 µg/kg·d. However, urinary deoxypyridinoline/creatinine was significantly reduced by 20% in OVX rats treated with lasofoxifene at 300 µg/kg·d compared with vehicle-treated OVX controls (Fig. 2B).
Ex vivo pQCT
A pQCT analysis of PTM showed that there was a 64% reduction in both trabecular bone content and trabecular bone density in OVX controls compared with sham controls 52 wk postsurgery (Fig. 3). Significant protection of trabecular bone content and trabecular density was observed in OVX rats treated with lasofoxifene at all doses. The trabecular bone mineral content of the PTM was significantly higher by 99–123%, and trabecular bone density was higher by 108–131% in lasofoxifene-treated groups compared with OVX controls (Fig. 3). Trabecular bone content and density in all lasofoxifene-treated OVX rats were still significantly lower than those in sham controls. No clear dose-response pattern was observed at the doses that were used in this study.
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). No other parameters listed in Table 1 differed between OVX and sham controls. These data indicate that the loss of trabecular bone volume in OVX rats was mainly due to the loss of trabecular number and increased separation, with little change in individual trabecular thickness. Further, bone resorption parameters (osteoclast surface and osteoclast number) and bone turnover parameter (bone formation rate/bone surface) in OVX controls did not differ from those in sham controls, indicating a new steady state of bone turnover after long-term (52-wk) OVX.
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). There were significantly higher trabecular bone volume (+204%, +224%, and +263% in 60, 150, and 300 µg/kg·d, respectively) and trabecular number, and significantly lower trabecular separation at all doses in lasofoxifene-treated OVX rats compared with OVX controls. Trabecular bone volume and trabecular number in all three dose groups of lasofoxifene-treated OVX rats were still significantly lower than those in sham controls. Furthermore, osteoclast number and osteoclast surface were significantly lower in all lasofoxifene-treated OVX rats compared with OVX controls, indicating that lasofoxifene decreased bone resorption in OVX rats. Osteoclast number at 300 µg/kg·d and osteoclast surface at 150 and 300 µg/kg·d in lasofoxifene-treated OVX rats were significantly lower compared with those in sham controls. There was no significant difference in osteoid surface at 60 and 150 µg/kg·d in lasofoxifene-treated OVX rats compared with both sham and OVX controls. Osteoid surface in the 300 µg/kg·d lasofoxifene-treated group was significantly higher than that in sham controls, but did not differ significantly from that in OVX controls. Osteoid width was significantly higher in all three dose groups compared with OVX controls, but did not differ significantly from that in sham controls. Mineralizing surface at 150 and 300 µg/kg·d in lasofoxifene-treated OVX rats was significantly lower compared with that in OVX controls but did not differ from that in sham controls. Mineral apposition rate and bone formation rate/bone surface referent did not significantly differ among the dose groups of lasofoxifene-treated OVX rats, OVX controls, and sham controls.
LV5 trabecular bone histomorphometry
As expected, OVX resulted in a significant reduction in trabecular bone volume (-66%) compared with sham controls (Table 2). The loss of trabecular bone volume was the result of a loss in trabecular thickness (-28%) as well as a loss in trabecular number (-56%). Osteoid surface, mineralizing surface, and bone formation rate/bone surface referent were significantly higher in OVX controls compared with sham controls. Osteoclast number and osteoclast surface had only small, nonsignificant increases after long-term (52-wk) OVX.
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Mechanical testing of LV4
Significant reductions in ultimate strength (-37%), energy (-46%), and toughness (-47%) were found in OVX controls compared with the sham controls 52 wk postsurgery, whereas stiffness did not differ between the two groups (Fig. 4).
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Reproductive tissues
Uterine weight was significantly reduced in OVX controls compared with sham controls (Fig. 5). Sham controls had relative uterine weight 456% that of OVX controls. Treatment with lasofoxifene at 60, 150, and 300 µg/kg·d for 52 wk resulted in slightly, but significantly, higher uterine weight. Uterine weight was higher by 16%, 20%, and 11% in the 60, 150, and 300 µg/kg·d lasofoxifene-treated OVX rats compared with OVX controls, respectively (Fig. 5).
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). The incidence of changes in the sham controls is consistent with age-related changes in rats as reported previously (26, 27). The OVX controls had an increased incidence of endometrial glandular dilatation and uterine epithelial atrophy (Table 3). A short columnar to cuboidal epithelium in the endometrium was characterized as epithelial atrophy. In lasofoxifene-treated OVX rats, endometrial glandular dilatation was observed in 23 of 24 animals in the 60 µg/kg·d group, in all 25 animals in the 105 µg/kg·d group, and in 10 of 25 animals in the 300 µg/kg·d group (Table 3).
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Mammary glands from OVX control rats had an increased incidence of atrophy (in 23 of 24 animals) compared with sham controls (zero of 25 animals). All lasofoxifene-treated rats showed atrophy in the mammary glands. Mammary gland changes in sham controls included glandular dilation (in four of 25 animals), lobular hyperplasia (in two of 25 animals), and fibroadenomas (in two of 25 animals). These changes in sham controls were considered normal aging changes (28).
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Discussion |
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The OVX rat model was chosen for this study because it shares many similarities with postmenopausal bone loss, as summarized by other investigators (19, 20, 21), and is thus recommended by the U.S. Food and Drug Administration as a test species for evaluating the long-term skeletal safety and efficacy of osteoporosis therapies (22). The expected responses of the rat OVX model were demonstrated in the current study. These include increased body weight, uterine atrophy, and decreased bone mass and strength. These findings are consistent with previous reports (19, 20, 21, 30, 31).
Wronski and colleagues (31) have previously described the long-term effects of OVX on rat proximal tibial metaphyseal trabecular bone histomorphometry. In the current study the development of osteopenia in long-term OVX rats was evidenced by multiple end points. At the tissue level, bone histomorphometry of both the PTM and LVB demonstrated the expected decline in trabecular bone volume after OVX. Architectural changes to the trabecular bone structure observed in this study were also an expected feature of the OVX-induced bone loss. In the PTM, trabecular number was decreased, and trabecular separation was increased. In the LVB, both trabecular number and thickness were decreased, and trabecular separation was increased. The tissue level changes in bone structure and histomorphometry in PTM were substantiated by pQCT analysis of the PTM, which showed a significant decrease in trabecular content and density. The mechanical strength of the LVB decreased significantly in OVX rats 52 wk postsurgery, indicating that prolonged estrogen deficiency did have a deleterious effect on bone strength in rats. Therefore, mechanical testing has been used to establish the effects of OVX and treatment on bone strength.
Urinary deoxypyridinoline and serum osteocalcin, markers of bone resorption and bone turnover, were significantly elevated in OVX rats at both 26 and 52 wk. However, the values at 52 wk were significantly lower than those at 26 wk, indicating that bone resorption and bone turnover in OVX rats returned toward the levels of sham controls after long-term (52-wk) estrogen deficiency. This was supported by trabecular bone histomorphometric analysis of the PTM and LVB, showing a nonsignificant increase in bone resorption parameters in OVX controls. Osteoid surface and mineralizing surface in both PTM and LVB, and bone formation rate/BS in LVB in OVX rats remained significantly higher than those in sham controls.
The primary objective of this study was to test the skeletal efficacy and safety of long-term (52-wk) treatment with lasofoxifene on OVX-induced loss of bone mass and strength in female Sprague Dawley rats. Long-term treatment of OVX rats with lasofoxifene had no adverse clinical events during the study that could be attributed to lasofoxifene treatment. In the uterus, lasofoxifene treatment was found to have no uterotropic effect, an undesirable side-effect seen in conventional estrogen replacement therapy. Biochemical bone turnover changes were examined after lasofoxifene treatment. At 26 wk, lasofoxifene treatment marginally reduced the elevated bone formation marker, serum osteocalcin, whereas treatment significantly reduced the bone resorption marker, urinary deoxypyridinoline. These results suggest that lasofoxifene has an antiresorptive action. This is in agreement with previous findings that lasofoxifene induces osteoclast apoptosis and reduces the number of multinuclear cells in rat bone marrow cell cultures (14). At 52 wk, due to the decreased levels of serum osteocalcin and urinary deoxypyridinoline from those observed at 26 wk in OVX controls, most lasofoxifene-treated OVX groups showed no significant difference from OVX controls in these markers, indicating that a new steady state of bone turnover was achieved. It is not clear why these markers in lasofoxifene-treated OVX rats were still significantly higher than those in sham controls after 26 wk, and in some doses even after 52 wk of treatment, as our early short-term studies showed that lasofoxifene at doses of 60 µg/kg·d or more completely prevented bone loss by inhibiting bone resorption and bone turnover in OVX rats (14, 29). As the most recent clinical studies (18) show an approximately 40% reduction in serum deoxypyridioline in postmenopausal women who received daily treatment with 0.25 or 1 mg lasofoxifene for 1 yr compared with the placebo group, serum bone markers from the long-term (52-wk) OVX rat study may not predict the clinical efficacy of an antiosteoporosis agent. In addition, as we discuss below, the bone strength of LVB in OVX rats treated with lasofoxifene at all three doses was completely preserved at levels not significantly different from those in sham controls.
Lasofoxifene treatment significantly reduced the loss of trabecular bone volume at the PTM and LVB seen in vehicle-treated OVX controls. This improvement in trabecular bone was achieved by preserving trabecular number in the PTM, and trabecular number and thickness in the LVB. Osteoclast number and osteoclast surface in the PTM at all three doses were significantly reduced by lasofoxifene treatment, confirming the antiresorptive effects of lasofoxifene. Interestingly, lasofoxifene increased osteoid width and decreased mineralizing surface to the levels in sham controls.
The beneficial actions of lasofoxifene on histomorphometric indexes of bone structure at the tissue level were substantiated at the organ level by ex vivo pQCT analysis of the PTM. Lasofoxifene-treated OVX rats displayed significantly higher trabecular bone mineral content and density than vehicle-treated OVX controls, which further confirmed lasofoxifene’s effectiveness in preventing trabecular bone loss. These results suggest that lasofoxifene is an effective agent in preventing estrogen deficiency-induced trabecular bone loss.
Although lasofoxifene’s ability to prevent OVX-induced deterioration of bone mass and architecture demonstrated its therapeutic potential, the therapeutic utility of an osteoporotic agent is dependent on its ability to reduce fracture incidence and risk. Biomechanical testing of the trabecular bone in the LVB has been used as a preclinical surrogate of bone quality and fracture efficacy. Lasofoxifene treatment was effective in preventing the loss of trabecular bone strength at the LVB due to estrogen deficiency. These findings confirm the utility of lasofoxifene treatment, as preservation of bone mass from estrogen deficiency was accompanied by improved bone strength compared with OVX controls.
There were no discernable differences among the three different doses of lasofoxifene in effects on any of the parameters tested. Therefore, the effects of the different doses used in the study will not be discussed. The data from the current study showed that although lasofoxifene at all three doses preserved bone strength at a level significantly higher than that in OVX controls and did not differ significantly from that in sham controls, trabecular bone volume at the LVB and PTM and trabecular bone content and density in the PTM in lasofoxifene-treated OVX rats were still significantly lower than those in sham controls. The possible explanation for the discrepancy between bone mass and bone strength might be that a mild low bone mass that does not affect connectivity would not alter mechanical properties of bone in lasofoxifene-treated OVX rats compared with sham controls.
Taken together, these observations indicate that the ability of lasofoxifene to prevent the OVX-induced reductions in bone mass, architecture, and bone strength is due to an inhibitory effect on bone resorption and bone turnover. These effects reverse the negative bone balance induced by OVX, thereby preventing bone loss and preserving bone strength.
The only significant treatment-related finding in the reproductive tissues in OVX rats was vaginal mucification, which was not progressive based on the current study and previous long-term studies. The uteri in OVX rats treated with either vehicle or lasofoxifene weighed less than those in the sham controls. This is consistent with uterine atrophy after OVX. The age-related changes observed in the sham controls were largely absent in the OVX rats treated with either vehicle or lasofoxifene. The uteri from lasofoxifene-treated rats weighed slightly more than the OVX controls and may correlate with an inhibition of the uterine epithelial atrophy observed. Mammary gland atrophy was also observed in OVX rats treated with either vehicle or lasofoxifene. It is likely that the slight increase in lasofoxifene uterine weight is due to fluid retention and the lack of endometrial epithelial atrophy are consistent with changes reported for other SERMs (32).
In summary, long-term OVX led to a significant decrease in BMD that was a result of increased bone turnover, with resorption exceeding formation. The OVX-induced osteopenia also led to decreases in the trabecular bone volume of the proximal tibia and lumbar vertebra that were accompanied by a profound deterioration of bone architecture. The architectural changes were severe enough to lead to significant reductions in bone strength. Treatment of OVX rats with lasofoxifene led to the prevention of loss of BMD at the trabecular bone-rich sites, of trabecular bone volume, and of trabecular number and a decrease in trabecular spacing. The mechanism of this positive effect on bone balance appears to be a consequence of inhibition of bone resorption and bone turnover in OVX rats. This leads to the preservation of bone biomechanical strength in OVX rats treated with lasofoxifene. These observations support the long-term efficacy and safety of lasofoxifene for the prevention and treatment of postmenopausal osteoporosis.
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Footnotes |
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Received October 31, 2003.
Accepted for publication January 5, 2004.
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M. B. Sporn Arzoxifene: A Promising New Selective Estrogen Receptor Modulator for Clinical Chemoprevention of Breast Cancer: Commentary re C. J. Fabian et al., Breast Cancer Chemoprevention Phase I Evaluation of Biomarker Modulation by Arzoxifene, a Third Generation Selective Estrogen Receptor Modulator. Clin Cancer Res 2004;10:5403-17. Clin. Cancer Res., August 15, 2004; 10(16): 5313 - 5315. [Full Text] [PDF]
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 N. Madamanchi, X. Liu, and M. S. Runge A New Slice of Pie?: Estrogen Regulation of Plasminogen Activator Inhibitor-1 Circ. Res., August 6, 2004; 95(3): 228 - 229. [Full Text] [PDF]
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 J. L. Turgeon, D. P. McDonnell, K. A. Martin, and P. M. Wise Hormone Therapy: Physiological Complexity Belies Therapeutic Simplicity Science, May 28, 2004; 304(5675): 1269 - 1273. [Abstract] [Full Text] [PDF]
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