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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 6 2197-2202
Copyright © 2000 by The Endocrine Society

From The Clinical Research Centers

A Comparison of the Effects of Raloxifene and Estrogen on Bone in Postmenopausal Women1

Karen M. Prestwood, Michele Gunness, Douglas B. Muchmore, Yili Lu, Mayme Wong and Lawrence G. Raisz

Center on Aging and Division of Endocrinology and Metabolism, University of Connecticut Health Center (K.M.P., L.G.R.), Farmington, Connecticut 06030; Pathology and Laboratory Medicine Service, Veterans Affairs Medical Center (M.G.), Portland, Oregon 97201; Lilly Research Laboratories, Eli Lilly & Co. (D.B.M., Y.L., M.W.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Karen M. Prestwood, M.D., Center on Aging, University of Connecticut Health Center, Farmington, Connecticut 06030-5215. E-mail: prestwood{at}nso1.uchc.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Raloxifene HCl, a selective estrogen receptor modulator, has been shown to increase bone mineral density (BMD) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus. However, it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level, nor how changes with raloxifene compare with estrogen. In this randomized, double blind study, we evaluated the effects of raloxifene (Evista, 60 mg/day) or conjugated equine estrogens (CEE; Premarin, 0.625 mg/day) on bone architecture, bone turnover, and BMD. Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for standard histomorphometric indexes. Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4, 10, 18, and 24 weeks of treatment. Total body, lumbar spine, and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry.

Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE, but not in the raloxifene, group. Bone mineralization did not change in either group. Most markers of bone resorption and formation decreased in both groups, but to a greater degree in the CEE group (P < .05). Total body and lumbar spine BMD increased from baseline in both groups, with a greater increase in the CEE group (P < 0.05). Hip BMD significantly increased from baseline in the raloxifene group, but the change was not different from that in the CEE group. These results suggest that raloxifene reduces bone turnover and increases bone density, although to a lesser extent than CEE. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS is a common disease in postmenopausal women and may lead to increased incidence of spine and hip fractures as well as excess morbidity associated with fracture. In the United States, an estimated 1.5 million fractures due to osteoporosis occur annually, and 12–20% of hip fractures are associated with mortality within 12 months (1). A 50-yr-old Caucasian woman has a 16% risk of hip fracture and a 32% risk of at least one nontraumatic vertebral fracture in her lifetime (2). Prevention of osteoporotic fracture is an important public health concern, and several agents are currently available for osteoporosis prevention and treatment (3).

Estrogen replacement therapy (ERT) is the mainstay of treatment for menopausal symptoms, as well as for the prevention and treatment of osteoporosis in postmenopausal women (4). Estrogen alone or combined with progestin in hormone replacement therapy (HRT) prevents bone loss as well as hip and spine fractures (5, 6, 7, 8). However, prolonged HRT use is associated with an increased relative risk of endometrial (9, 10) and breast cancer (11, 12). Uterine bleeding, breast pain, and fear of breast cancer are frequently cited as reasons for women to refuse initial therapy or to discontinue HRT early. Thus, for many women, the long-term skeletal benefits of HRT are not realized.

Raloxifene is a benzothiophene-derived selective estrogen receptor modulator (SERM) with estrogen agonist effects on the skeleton and serum lipids and with estrogen antagonist activity on endometrial and breast tissue (13). In estrogen-deficient ovariectomized rats, raloxifene administration is associated with increased bone mineral density (BMD), decreased bone turnover, maintenance of normal bone architecture, and decreased serum cholesterol without stimulating the endometrium (14, 15, 16, 17, 18, 19). In clinical studies of postmenopausal women, raloxifene also had favorable effects on bone and lipid metabolism without adversely affecting endometrial tissue (20, 21, 22, 23).

Like estrogen, raloxifene affects bone turnover and is used for the prevention and treatment of postmenopausal osteoporosis. It is not known whether these changes in bone turnover are associated with effects at the tissue level. The primary objective of this study was to compare the short-term effects of raloxifene and conjugated equine estrogens (CEE) on bone histomorphometry, BMD, and biochemical markers of bone turnover. We hypothesized that raloxifene would have effects similar to those of CEE on the above parameters.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

This was a phase II, randomized, double blind study. Women who participated in the study were at least 5 yr postmenopausal, between the ages of 55–85 yr inclusive, with lumbar spine BMD between 1 SD above to 3 SD below peak bone mass. All subjects were Caucasian and were studied as out-patients. Exclusion criteria included 1) use of estrogen, calcitonin, systemic corticosteroids, or progestins within the last 6 months; 2) history of vertebral or hip fractures or presence of spinal osteoarthritis or scoliosis; 3) any previous use of fluoride or bisphosphonate therapy; 4) history of any cancer within the past 5 yr, thromboembolic disorders, or abnormal uterine bleeding; 5) dietary calcium intake less than 500 mg/day or more than 1500 mg/day; and 6) systemic disease or unresolved endocrine disorders that could potentially affect bone turnover or lipids. The local institutional review board approved the protocol, and informed written consent was obtained from all participants.

After an initial screening visit, the 51 eligible volunteers were randomly assigned to 6 months of treatment with either 60 mg/day raloxifene HCl (Evista, Eli Lilly & Co., Indianapolis, IN) or 0.625 mg/day CEE (Premarin, Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA). Women with an intact uterus received 5 mg/day medroxyprogesterone acetate (Provera, Upjohn Co., Kalamazoo, MI) for 14 days at the end of the 6-month treatment phase. The occurrences of adverse events and discontinuations were noted at each follow-up visit.

Bone biopsy

Anterior iliac crest bone biopsies were performed at baseline and after 6 months of treatment using a 2.5-mm Jamshidi needle. Beginning 20 days before the bone biopsy date, subjects underwent double tetracycline labeling with demeclocycline HCl (Declomycin, Lederle Laboratories Division, American Cyanamid, Pearl River, NY). Demeclocycline (300 mg) was taken every 8 h for 3 days (days 1–3), followed by an 11-day drug-free interval, a second 3-day course of demeclocycline (300 mg every 8 h, on days 15–17), and 3 drug-free days before biopsy. Both baseline and endpoint biopsies had to be adequate for a woman to be included in the histomorphometric analysis.

Bone histomorphometry

Bone biopsy specimens were immediately fixed in 70% ethanol, transported to the laboratory, dehydrated in ascending concentrations of ethanol, and embedded in methyl methacrylate. Sections were cut from two different levels of the bone core at 5 and 10 µm with a Reichert-Jung Polycut S microtome (Leica Corp., Deerfield, IL). The 5-µm sections were stained with toluidine blue and Goldner’s Trichrome and mounted with Permount, whereas the 10-µm sections were mounted unstained for fluorescent microscopy of the tetracycline labels. Histological parameters of bone structure, resorption, and formation were measured on a Axiophot microscope (Carl Zeiss, Thornwood, NY) using the Roche Pathology Workstation image analysis system (Autocyte, Elon College, NC) with semiautomatic and automatic software (KS400, Kontron Instruments Ltd., Munich, Germany). Bone was assessed qualitatively by evaluating the presence or absence of marrow fibrosis and woven bone. Nomenclature and calculations of histomorphometric indexes follow standards established by the American Society for Bone and Mineral Research (24).

Histomorphometry of the cancellous bone was performed on at least two stained 5-µm sections from both levels, so that a minimum of 10 mm2 of tissue area (range, 10–38 mm2) was measured, giving 30–129 mm of bone surface. Bone volume was measured at a magnification of x156, and the surface-based parameters were measured at a magnification of x400. Static histomorphometric indexes were cancellous bone volume (BV/TV; percentage of tissue area), osteoid volume (OV/BV; percentage of bone area), trabecular thickness (Tb.Th; calculated according to the parallel plate model), and trabecular number (Tb.N). Osteoid surface (OS/BS), osteoblast surface (Ob.S/BS), and osteoclast surface (Oc.S/BS) were measured as a percentage of the bone surface, whereas the number of osteoclasts (OcN) along the bone surface was expressed as number per mm2 tissue area. Osteoid thickness (O.Th) was measured directly along the osteoid seams. Wall thickness (W.Th) was measured directly on completed bone packets using polarized light. Both osteoid thickness and wall thickness were corrected for section obliquity using {pi}/4.

Dynamic parameters were measured from the tetracycline labels on four unstained sections at a magnification of x625. Mineralizing surface (MS/BS) was calculated as the percentage of bone surface with double plus half-single labels. The surface-based bone formation rate (BFR/BS; cubic millimeters per mm2/yr) was calculated as [(MAR x 0.365) x MS/BS]/100, where the mineral apposition rate (MAR) was determined by dividing the interlabel distance by the interval labeling time. Interlabel distance was measured in a similar manner to osteoid width and corrected for section obliquity. Bone formation rate was also referenced to bone volume (BFR/BV) and tissue volume (BFR/TV) and expressed as percentage per yr. The activation frequency of new remodeling units (Ac.F; per yr) was calculated as BFR/BS divided by W.Th.

Bone density measurement

Total body, lumbar spine, femoral neck, trochanter, and Ward’s triangle BMD were measured by dual energy x-ray absorptiometry (Lunar Corp., Madison, WI) at baseline and at the end of the treatment phase. The in vivo coefficients of variation in BMD measurements in postmenopausal women were total body, 1.1%; total hip, 1.1%; femoral neck, 1.7%; and lumbar spine, 1.6%.

Biochemical markers of bone turnover

Biochemical markers of bone turnover were measured in serum and urine collected at baseline and at 4, 10, 18, and 24 weeks of treatment. Samples were analyzed at the General Clinical Research Center Core Laboratory at the University of Connecticut or at Corning SciCor, Inc. (Indianapolis, IN). Markers of bone formation were serum bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and C-terminal type I procollagen peptide (CICP). The markers of bone resorption were urinary cross-linked N- and C-telopeptides of type I collagen (NTx and CTx, respectively) and free deoxypyridinoline cross-links (Dpyr). CICP, NTx, CTx, and Dpyr were measured by enzyme-linked immunosorbent assay (Metra Biosystems, Mountain View, CA; Ostex International, Inc., Seattle, WA; Osteometer A/S, Copenhagen, Denmark; and Metra Biosystems, Mountain View, CA) at the General Clinical Research Center Core Laboratory. BSAP and OC were measured by RIA (Hybritech, Inc., San Diego, CA; and CIS Biointernational, Gif-sur-Yvette, France, respectively) at Corning SciCor, Inc. All markers of bone resorption and CICP were measured in batched urine and serum; sera used for measurement of BSAP and OC were not batched. The intra- and interassay precisions were less than 10% for all markers.

Statistical methods

All analyses were conducted on an intent to treat basis for measurements of bone histomorphometry parameters, BMD, and biochemical markers of bone turnover. Data from the subjects who had a baseline and at least one postbaseline measurement were included in the baseline to end-point change and percent change analyses, with missing values handled by carrying their last values forward. Results for all efficacy variables were expressed as the mean percent change from baseline, except for the histomorphometry parameters, which had large variations in the percent change due to outliers. Therefore, results for the histomorphometry parameters are presented as absolute and median changes from baseline. Differences between treatment groups were evaluated by one-way ANOVA. For BMD and biochemical markers of bone turnover, within-group changes were assessed by Student’s t test. For histomorphometric parameters, within-group changes were assessed by the Wilcoxon signed rank test. Both raw data and rank-transformed data were analyzed using the same model, and the statistical inference was reported from the raw data when no contradiction was observed. The incidences of adverse events and discontinuation rates were analyzed by the {chi}2 test. Differences between treatment groups were tested at a two-sided significance level of 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The baseline characteristics of the women randomly assigned to treatment were not statistically different between groups (Table 1Go). Alcohol intake of more than three drinks per week was noted in 24% of the study subjects, and 16% of the subjects were current smokers. The rate of compliance, as measured by pill count, ranged between 94–97% for both treatment groups and was not statistically different. The incidence of discontinuations due to adverse events was significantly higher in the CEE group (6 of 26) than in the raloxifene group (1 of 25). Subjects in the CEE group discontinued the study due to breast pain, chest pain, endometrial hyperplasia, pulmonary embolus, meningitis, and scheduling conflicts. One subject in the raloxifene group discontinued due to depression.


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  		Table 1. Baseline subject characteristics

 
None of the 44 women who completed the study refused a second biopsy attempt. Twenty-three women had biopsy pairs that were adequate for evaluation; 14 women had inadequate biopsy at baseline, 4 with inadequate biopsy at 6 months and 3 with inadequate biopsy tissue at both time points. Of the 23 pairs of biopsies available for analysis, 12 pairs were in the raloxifene group, and 11 pairs were in the CEE group. At baseline, there were no significant differences between the raloxifene and CEE treatment groups in the static indexes (Table 2Go). BV/TV, OV/BV, Tb.Th, O.Th, and W.Th did not change in either treatment group. Ob.S/BS and Oc.N were significantly decreased from baseline in the CEE group (Table 2Go), but not the raloxifene group. The changes in Ob.S/BS and Oc.N were not significantly different between the treatment groups.


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  		Table 2. Changes in static histomorphometric parameters

 
The dynamic histomorphometric indexes BFR/BV, BFR/BS and Ac.F were significantly decreased from baseline to end point in the CEE group, but not in the raloxifene group (Table 3Go). The change in Ac.F was also significantly different between therapy groups, with CEE having a greater effect. MS/BS and MAR did not change in either treatment group.


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  		Table 3. Changes in dynamic histomorphometric parameters

 
Most markers of bone turnover decreased from baseline to end point in both treatment groups. CTx decreased by 23% from baseline to end point in the raloxifene group, compared with a 53% decrease in CEE group. NTx decreased 43% with CEE treatment and 22% with raloxifene treatment. The decreases in CTx and NTx were significantly different between treatment groups throughout the study. Dpyr decreased 16% in the raloxifene group and 15% in the CEE group, with no differences between groups. The bone formation markers decreased significantly from baseline in the CEE group; CICP decreased 21%, OC decreased 25%, and BSAP decreased 37%. In the raloxifene group, BSAP at the end point was also significantly decreased from the baseline value. For most bone turnover markers, the mean changes at each time point were significantly greater in the CEE group than in the raloxifene group (Figs. 1Go and 2Go).



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  		Figure 1. Urinary biochemical markers of bone resorption in postmenopausal women treated for 6 months with 60 mg/day raloxifene (RLX; n = 25) or 0.625 mg/day CEE (n = 26). Values for CTx (A), NTx (B), and free Dpyr (C) are normalized with respect to creatinine and expressed as mean percent change from baseline ± SE. a, Significant differences from baseline (P < 0.05); b, significant differences between groups (P < 0.05).

 


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  		Figure 2. Serum biochemical markers of bone formation in postmenopausal women treated for 6 months with 60 mg/day raloxifene (RLX; n = 25) or 0.625 mg/day CEE (n = 26). Values for BSAP (A), OC (B), and CICP (C) are expressed as the mean percent change from baseline ± SE. a, Significant differences from baseline (P < 0.05); b, significant differences between groups (P < 0.05).

 
Significant differences between groups were seen in lumbar spine and total body BMD, with CEE having an approximately 2-fold greater effect than raloxifene (Fig. 3Go). Women who were assigned to raloxifene had significant increases in BMD in the total body, lumbar spine, and the proximal femur compared to baseline. In the CEE group, the total body and lumbar spine, but not the proximal femur BMD, were significantly increased from baseline. Although the increases in BMD at all proximal femoral sites were greater with raloxifene than with CEE, these differences were not statistically significant.



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  		Figure 3. BMD was measured by dual energy x-ray absorptiometry at various skeletal sites in postmenopausal women treated for 6 months with 60 mg/day raloxifene (RLX; open bars; n = 24) or 0.625 mg/day CEE (hatched bars; n = 19). All values are expressed as the mean percent change from baseline ± SE. a, Significant difference from baseline (P < 0.05); b, significant difference between groups (P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates that 6-month treatment with raloxifene or CEE decreased bone turnover, as estimated by bone histomorphometry and biochemical markers of bone turnover. However, the reductions in bone turnover were quantitatively greater in the CEE group, suggesting that raloxifene has a comparable, but smaller, effect. Further, raloxifene and CEE maintained bone architecture to a similar extent, as indicated by comparable trabecular number and thickness at the end point, and there was no evidence of marrow fibrosis or woven bone in either group. In this study the decreases in bone formation rates and activation frequency in the CEE group were slightly, but not significantly, greater than the decreases in the raloxifene group. The Ac.F in the CEE group in this study was decreased to levels similar to those observed with longer term CEE treatment, but changes in BFR/BS with CEE were somewhat smaller than changes observed with longer estrogen treatment (25, 26). The lack of change in MAR in both CEE and raloxifene groups suggests that mineralization is not adversely affected by either therapy. Studies in animals suggest that raloxifene and estrogen are equally effective in maintaining cancellous bone volume and that changes in histomorphometric parameters may occur later than changes in BMD or bone turnover (14, 16, 17, 18, 19). Data from the current study support the animal studies and suggest that a 6-month treatment period may not be long enough to produce the full extent of histological changes in response to raloxifene therapy. Our data are limited by the small sample size for histomorphometric measures. This small sample size was not related to women refusing a biopsy, but was due to the inadequacy of tissue obtained in a number of biopsies, as detailed in Results. Nonetheless, changes in histomorphometric parameters in this study are similar to those reported for CEE by previous investigators and demonstrate that raloxifene has lesser effects than CEE on bone turnover, as estimated by histomorphometry.

Most markers of bone turnover decreased in both treatment groups, with CEE having a greater effect at 6 months. These data suggest that raloxifene has a similar effect on bone metabolism as estrogen, albeit smaller. The changes in markers of bone turnover demonstrated in this study are similar in magnitude to the changes reported in other studies in which raloxifene and estrogen were studied separately (20, 27, 28).

BMD significantly increased in both treatment groups within the 6-month study period, with CEE having a greater increase. The increase in lumbar spine BMD in the raloxifene-treated group in this study was similar to that seen at 6 months in a larger 2-yr raloxifene trial. The increase in femoral neck BMD in the raloxifene group of this study was greater than that previously observed in the 2-yr raloxifene study (20). These apparent differences probably result from the variability in BMD values resulting from the small sample size in this study. Interestingly, therapy with raloxifene (60 mg/day) for 2 yr (20) or with CEE for 6 months in this study increased total body BMD to the same degree, indicating that a longer treatment period may be required for raloxifene to achieve its effects on total body bone density.

The clinical significance of the differences between the effects of raloxifene and CEE on BMD and markers of bone turnover in terms of fracture risk is unknown. Although numerous studies have demonstrated that ERT prevents bone loss and reduces bone turnover in postmenopausal women (7, 27, 28, 29), and epidemiological studies (5, 6, 8) suggest that ERT reduces fracture risk, few prospective clinical trials have verified this reduced fracture risk (29). However, recent data from raloxifene trials demonstrate reductions in incident vertebral fractures among women with osteoporosis (30) that are similar to the reductions seen with alendronate (31) despite quantitatively smaller effects on BMD and bone turnover markers. Indeed, the effects on BMD of alendronate treatment significantly underestimate the fracture efficacy observed in the clinical trial (32). These observations suggest that the fracture efficacy of antiresorptive agents is not fully predicted by changes in BMD or bone turnover markers, and effects on bone architecture or quality may also contribute to fracture efficacy.

From this study we conclude that raloxifene has smaller effects on bone turnover and bone density than CEE. However, raloxifene therapy was associated with fewer side-effects than CEE and in other studies has been shown to reduce the incidence of new fractures. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.


   Acknowledgments
 
We gratefully acknowledge the work of Bertha Robbins and Tom Shepherd, research facilitators at the University of Connecticut Health Center General Clinical Research Center and Center on Aging, and Sonia Dandridge, clinical research associate at Lilly Research Laboratories. The authors also thank Masahiko Sato, Ph.D., and Hunter Heath, M.D., of Lilly Research Laboratories for their critical reviews of this manuscript.


   Footnotes
 
1 This work was supported by NIH Grant M01-RR-06192 (to University of Connecticut Health Center General Clinical Research Center) and Eli Lilly & Co. (Indianapolis, IN). Back

Received June 25, 1999.

Revised February 9, 2000.

Accepted February 15, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Riggs BL. 1991 Overview of osteoporosis. West J Med. 154:63–77.[Medline]
  2. Cummings SR, Black DM, Rubin SM. 1989 Lifetime risks of hip, Colles’, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med. 149:2445–2448.[Abstract/Free Full Text]
  3. Prestwood KM, Kenny AM. 1998 Osteoporosis: pathogenesis, diagnosis and treatment in older adults. In: Loeser Jr RF, ed. Clinics in geriatric medicine: musculoskeletal and connective tissue disorders, 14th Ed. Philadelphia: Saunders; 577–599.
  4. Byyny RL, Speroff L. 1996 A clinical guide for the care of older women. primary and preventive care. Baltimore: Williams & Wilkins.
  5. Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR. 1980 Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med. 303:1195–1198.[Abstract]
  6. Kiel DP, Felson DT, Anderson JJ, Wilson PW, Moskowitz MA. 1987 Hip fracture and the use of estrogens in postmenopausal women. The Framingham Study. N Engl J Med. 317:1169–1174.[Abstract]
  7. Lindsay R, Tohme JF. 1990 Estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol. 76:290–295.[Medline]
  8. Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. 1995 Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 122:9–16.[Abstract/Free Full Text]
  9. Beresford SA, Weiss NS, Voigt LF, McKnight BS. 1997 Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet. 349:458–461.[CrossRef][Medline]
  10. Grady D, Rubin SM, Petitti DB, et al. 1992 Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 117:1016–1037.
  11. Collaborative Group on Hormonal Factors in Breast Cancer. 1997 Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108411 women without breast cancer. Lancet. 350:1047–1059.[CrossRef][Medline]
  12. Colditz GA, Hankinson SE, Hunter DJ, et al. 1995 The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 332:1589–1593.[Abstract/Free Full Text]
  13. Khovidhunkit W, Shoback DM. 1999 Cinical effects of raloxifene hydrochloride in women. Ann Intern Med. 130:431–439.[Abstract/Free Full Text]
  14. Evans G, Bryant HU, Magee D, Sato M, Turner RT. 1994 The effects of raloxifene on tibia histomorphometry in ovariectomized rats. Endocrinology. 134:2283–2288.[Abstract/Free Full Text]
  15. Evans GL, Bryant HU, Magee DE, Turner RT. 1996 Raloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology. 137:4139–4144.[Abstract]
  16. Sato M, Bryant HU, Iversen P, et al. 1996 Advantages of raloxifene over alendronate or estrogen on nonreproductive and reproductive tissues in the long-term dosing of ovariectomized rats. J Pharmacol Exp Ther. 279:298–305.[Abstract/Free Full Text]
  17. Black LJ, Sato M, Rowley ER, et al. 1994 Raloxifene (LY139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest. 93:63–69.
  18. Frolik CA, Bryant HU, Black EC, Magee DE, Chandrasekhar S. 1996 Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: effects of raloxifene HCl, tamoxifen, estrogen, and alendronate. Bone. 18:621–627.[Medline]
  19. Sato M, Rippy MK, Bryant HU. 1996 Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J. 10:905–912.[Abstract]
  20. Delmas PD, Bjarnason NH, Mitlak BH, et al. 1997 Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 337:1641–1647.[Abstract/Free Full Text]
  21. Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C. 1996 A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 11:835–842.[Medline]
  22. Heaney RP, Draper MW. 1996 Raloxifene mimics estrogen in human bone remodeling kinetics. J Bone Miner Res 11:S446–T586.
  23. Boss SM, Huster WJ, Neild JA, Glant MD, Eisenhut CC, Draper MW. 1997 Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am J Obstet Gynecol. 177:1458–1464.[CrossRef][Medline]
  24. Parfitt AM, Drezner MK, Glorieux FH, et al. 1987 Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2:595–610.[Medline]
  25. Steiniche T, Hasling C, Charles P, Eriksen EF, Mosekilde L, Melsen F. 1989 A randomized study on the effects of estrogen/gestagen or high dose oral calcium on trabecular bone remodeling in postmenopausal osteoporosis. Bone. 10:313–320.[Medline]
  26. Vedi S, Compston JE. 1996 The effects of long-term hormone replacement therapy on bone remodeling in postmenopausal women. Bone. 19:535–539.[Medline]
  27. Prestwood KM, Pilbeam CC, Burleson JA, et al. 1994 The short-term effects of conjugated estrogen on bone turnover in older women. J Clin Endocrinol Metab. 79:366–371.[Abstract]
  28. Prestwood KM, Thompson DL, Kenny AM, Seibel MJ, Pilbeam CC, Raisz LG. 1999 Low dose estrogen and calcium have an additive effect on bone resorption in older women. J Clin Endocrinol Metab. 84:179–183.[Abstract/Free Full Text]
  29. Lufkin EG, Wahner HW, O’Fallon WM, et al. 1992 Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 117:1–9.
  30. Ettinger B, Black D, Mitlak BH, et al. 1999 Reduction of vertebral fracture risk in postmenopuasal women with osteoporosis treated with raloxifene. JAMA. 282:637–645.[Abstract/Free Full Text]
  31. Black DM, Cummings SR, Karpf DB, et al. 1996 Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 348:1535–1541.[CrossRef][Medline]
  32. Cummings SR, Black DM, Vogt TM for the FIT Research Group. 1996 Changes in BMD substantially underestimate the anti-fracture effects of alendronate and other antiresorptive drugs. J Bone Miner Res. 11(Suppl 1):S102.



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[Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

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 J Child NeurolHome page
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[Abstract] [PDF]

Home page
 The Annals of PharmacotherapyHome page
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[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
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[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4476 - 4481.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
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Additive Effects of Raloxifene and Alendronate on Bone Density and Biochemical Markers of Bone Remodeling in Postmenopausal Women with Osteoporosis
J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 985 - 992.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
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[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
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Effects of Long-Term Use of Raloxifene, a Selective Estrogen Receptor Modulator, on Thyroid Function Test Profiles
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[Full Text] [PDF]

Home page
 JAMAHome page
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