Raloxifene n Osteoporosis

7/29/2019 Raloxifene n Osteoporosis

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Treatment of Established Postmenopausal Osteoporosis

with Raloxifene: A Randomized Trial

EDWARD G. LUFKIN,1 MICHAEL D. WHITAKER,2 THOMAS NICKELSEN,3 RODOLFO ARGUETA,2

ROBERT H. CAPLAN,4 RONALD K. KNICKERBOCKER,3 and B. LAWRENCE RIGGS1

ABSTRACT

Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor

antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascularsystems. We conducted a 1-year prospective, randomized, double-blind trial in 143 postmenopausal osteoporotic

women (mean SD age, 68.4 5.0 years) with at least one prevalent vertebral fractures and low bone mineral

density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a

control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no

differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or

increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values

over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase ( 14.9%,

8.87%), serum osteocalcin ( 20.7%, 17.0%), and urinary C-telopeptide fragment of type I collagen/creatinine

( 24.9%, 30.8%), markers of bone turnover; for serum total cholesterol ( 7.0% for RLX60) and low density

lipoprotein cholesterol (LDL) ( 11.4% for RLX60) and for the LDL/HDL cholesterol ratio ( 13.2%, 8.3%).

BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were

nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (forRLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff,

there was a dose-related reduction (p 0.047). We conclude that raloxifene therapy is well tolerated, reduces

serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the

conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy.

(J Bone Miner Res 1998;13:17471754)

INTRODUCTION

RALOXIFENE HYDROCHLORIDE is a benzothiophene deriva-tive, originally investigated as a treatment for advanced

breast cancer.(1) It is related pharmacologically, but not

chemically, to the more widely used antiestrogen tamoxifen.

These drugs are now classified as selective estrogen recep-

tor modulators based on their tissue-specific effects in clas-

sical target tissue for estrogen action(2) and, at least for

raloxifene, on the presence of a specific response element in

DNA that differs from the classical estrogen response ele-

ment.(3) This selective action was first associated with ta-

moxifen treatment. Despite its action as an antiestrogen onbreast tissue, tamoxifen was reported to maintain bone

mass in postmenopausal women, to lower serum choles-

terol, and to stimulate endometrial proliferation.(46) How-

ever, clinical use of tamoxifen to treat osteoporosis is lim-

ited by its toxicity, including induction of endometrial

hyperplasia and carcinoma, thrombophlebitis, abnormal he-

patic function and, in rodents, hepatic tumors.(5)

1Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, U.S.A.2Division of Endocrinology, Mayo Clinic, Scottsdale, Arizona, U.S.A.3Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, U.S.A.4

Section of Endocrinology, Gundersen Clinic, La Crosse, Wisconsin, U.S.A.

JOURNAL OF BONE AND MINERAL RESEARCHVolume 13, Number 11, 1998Blackwell Science, Inc. 1998 American Society for Bone and Mineral Research

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In contrast to results with tamoxifen, studies in experi-mental animals and in humans treated with raloxifene havenot demonstrated major adverse actions. Moreover, liketamoxifen, it has antiresorptive effects on bone, but, unliketamoxifen, it does not cause endometrial stimulation. Thus,Black et al.(7) found that raloxifene treatment of ovariecto-mized rats prevented bone loss, reduced serum cholesterol,

and prevented estrogen-induced endometrial hyperplasia.In an 8-week study in early postmenopausal women, Draperet al.(8) found that raloxifene in dosages of 200 mg/day or600 mg/day and conjugated equine estrogen both had sim-ilar effects on reducing biochemical markers of bone turn-over versus placebo. Raloxifene also decreased serum lipidsand, as assessed by endometrial biopsies, did not stimulatethe endometrium. There were no adverse effects except forhot flushes, which were common, especially in the groupreceiving the highest dosage of raloxifene.

Based on these favorable results, raloxifene appears to be apromising candidate drug for the treatment of postmeno-pausal osteoporosis. We therefore initiated a 1-year prospec-

tive, randomized, double-blind clinical trial in women withestablished postmenopausal osteoporosis comparing paralleltreatment groups of controls and two dosages of raloxifene.

MATERIALS AND METHODS

Study population

One hundred and forty-three women with postmeno-pausal osteoporosis were enrolled in the clinical trial. All ofthem were studied at the Mayo Clinic, Rochester, MN, orthe Mayo Clinic, Scottsdale, AZ, including the women re-cruited at the Gundersen Clinic in La Crosse, WI, who were

studied at the Mayo Clinic, Rochester. Subjects were eligi-ble if they were in good health except for osteoporosis, freeof any serious acute or chronic medical condition that mightaffect bone or calcium metabolism, fully ambulatory, be-tween the ages of 45 and 75 years, and postmenopausal (nomenses for 5 years or levels of serum estradiol 73 pmol/land serum follicle-stimulating hormone [FSH] 30 IU/l).Specific exclusion criteria included patients with a history ofdeep venous thrombosis, thromboembolic disorders, or ce-rebral vascular accident, also patients with a history ofcancer within the previous 5 years, except for superficialskin cancer. The criteria for the diagnosis of osteoporosiswere a bone mineral density (BMD) value for either the

lumbar spine or proximal femur of 10th percentile fornormal premenopausal females and one or more nontrau-matic vertebral fractures, defined as a decrease in verticalheight of15% compared with adjacent vertebrae. (Twowomen were inadvertently entered whose BMD values wereslightly above the entry criteria.) Calcium supplements of500 mg/day or vitamin D 800 IU/day were allowed.Patients with previous estrogen replacement therapy (ERT)or calcitonin therapy were accepted after a 6-month wash-out interval before enrollment, and, for larger dosages ofcalcium supplements or vitamin D supplements, after a3-month washout interval. Patients were ineligible if theyhad been previously treated with sodium fluoride or

bisphosphonates.

Experimental design

Candidates for the trial were seen for a screening visit todetermine eligibility, at which time they had a generalmedical examination that included physical examination,including breast examination, general laboratory studies,radiographic evaluation of the thoracic and lumbar spine,

and mammograms. All details of the study were explained,and informed written consent was obtained from all partic-ipants. One hundred and forty-three women were thenassigned to parallel groups receiving no drug (control,CON), 60 mg/day of raloxifene HCl (RLX60), or 120 mg/day of raloxifene HCl (RLX120) by blocked random allo-cation. All women concomitantly received a supplementaldosage of 750 mg/day elemental calcium and supplementsof vitamin D, to bring daily intake to 800 IU. During a12-month treatment period, they were evaluated four times:at baseline, 1 month, 6 months, and 12 months. At eachvisit, the women received interviews, determination of vitalsigns, and measurements of bone densitometry, bone bio-

chemical markers, serum lipids, and serum intact parathy-roid hormone (PTH). Serum vitamin D metabolites weremeasured at baseline, 1 month, and 1 year. Transvaginalultrasonography to determine endometrial thickness wasobtained at baseline and 12 months. At 1 year, spinal ra-diographs and mammograms were repeated.

Laboratory methods

Serum osteocalcin (ELSA-OSTED, CIS BioInterna-tional, Gifs-sur-Yvette, France), serum bone-specific alka-line phosphatase (ALP; Hybritech, Inc., San Diego, CA,U.S.A.), and C-terminal telopeptide of type I collagen

(CTx; ACTIVE CrossLaps; Diagnostic Systems Laborato-ries, Inc., Webster, TX, U.S.A.) in a first-morning voidedurine sample were measured by enzyme-linked immunosor-bent assay kits. Four serum lipid variables were measured(serum total cholesterol, serum triglycerides, serum highdensity lipoprotein [HDL], and low density lipoprotein[LDL] cholesterol). Serum PTH was measured by a two-siteimmunoradiometric assay (Incstar Corp., Stillwater, MN,U.S.A.). Serum 25-hydroxyvitamin D and 1,25-dihydroxyvi-tamin D were measured by the method of Kao and He-ser.(9) Serum and urine samples were stored at 70C untilmeasured in a central laboratory (Covance Central Labo-ratory Services, Inc., Indianapolis, IN, U.S.A.). BMD at the

anteroposterior and lateral lumbar spine, total hip, distalone-third radius, and ultradistal radius, and total body bonemineral were measured by dual-energy X-ray absorptiom-etry using a scanner (QDR-2000; Hologic, Inc., Waltham,MA, U.S.A.). For assessment of vertebral fractures, lateralradiographs of the lumbar and thoracic spine were obtainedat a standard target-to-film distance of 122 cm. For thevertebrae from T4 to L5, eight points were placed to definethe anterior, posterior, right lateral, and left lateral heightsof the vertebrae. The points were electronically digitized,and the heights were assessed by computer as previouslydescribed.(10)A prevalent (present at baseline) fracture wasdefined as a decrease in one or more of the four vertical

heights of15% compared with those of adjacent verte-

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brae. An incident (new) fracture (change between baselineand 1 year), was defined as 15% decrease in the samevertebra between baseline and 1 year. A more stringent

definition of incident and prevalent fractures was also ap-plied, defined as a30% decrease in the same four verticalheights. Precision of densitometry was monitored using aphantom exchanged between the two sites. The coefficientof variation for the Rochester site was 0.46, and 0.44 for theScottsdale site.

Statistical methods

All data analyses were performed with the intent to treatpopulation with missing values handled by carrying theirlast value forward. Continuous laboratory data were ana-lyzed using an analysis of variance model including treat-

ment and investigative site. This model was fit using the rawchange and percentage change from baseline to the end ofthe study for BMD and fracture rates. The change andpercentage change data were ranked and analyzed in themodel above for the biochemical markers, which are some-times skewed. All p values and inferences were based onpairwise comparisons using the percentage change data forthe model described above. Categorical data were analyzedacross treatment groups using Pearsons chi-square test.Additionally, for the vertebral fracture analysis, trend testswere performed using a linear contrast for the fracture ratesand the gamma statistic for the categorical data.

To assess the possibility of a differential treatment effect

in the two investigational sites, both change and percentagechange from baseline to endpoint were modeled using anal-ysis of variance with terms for treatment, site, and treat-ment-by-site interaction. In no case was the treatment-by-site interaction term significant, thus it was removed fromthe model. Baseline BMD levels were generally slightlyhigher in the Scottsdale site.

RESULTS

Clinical findings

The groups did not differ at baseline regarding the gen-

eral characteristics, except for minor variations in age and

alcohol usage ( Table 1). Thirteen patients did not completethe first year of study. One woman in the RLX60 groupdied of unrelated causes (pneumonia), two discontinued for

personal reasons, two because of protocol variance, andeight because of adverse effects. The percentage of patientsreporting at least one serious adverse event (as defined byFood and Drug Administration criteria) was not signifi-cantly different among the three groups. Specifically, therewere no differences in the occurrence of uterine bleeding,thrombophlebitis, pulmonary embolism, breast abnormali-ties, or increased endometrial thickness or other endome-trial pathological findings. Results of mammographyshowed no adverse effects of raloxifene treatment on breasttissue. The mean SE for endometrial thickness as as-sessed by ultrasonography was not significantly differentamong treatment groups (CON, 3.39 0.34 mm; RLX60,

2.76 0.34 mm; and RLX120, 2.83 0.39 mm at baseline;and CON, 3.67 0.66 mm; RLX060, 3.03 0.40 mm; andRLX120, 2.55 0.31 mm at 1 year).

Laboratory measurements

The results of BMD measurements are given in Table 2for the groups receiving no drug (CON), raloxifene HCl60 mg/day (RLX60), and raloxifene HCl 120 mg/day(RLX120). Compared with the CON group, the RLX60group improved significantly at the total hip scanning site,and both RLX groups improved at the distal and ultradistal

radius scanning site. There were nonsignificant trends to-ward increased BMD or decreased bone loss with RLXversus CON treatment at all scanning sites except at thelateral lumbar spine.

The effects of RLX treatment on biochemical markersfor bone turnover and for serum intact PTH are shown inTable 3. Compared with the CON group, there were signif-icant decreases in both treatment groups in both serumbone-specific ALP and serum osteocalcin, markers of boneformation, and in the urinary CTx/Cr ratio, a marker ofbone resorption. Consistent with the decrease in bone re-sorption, there was a significant compensatory increase inserum PTH. These changes were significant at 6 months

but not maximal until 12 months. Values for serum 25-

TABLE 1. CHARACTERISTICS OF PARTICIPANTS AT BASELINE (MEAN SE)

Variables

Treatment groups

pCON RLX60 RLX120

n 48 48 47Age (years) 68.2 0.7 69.9 0.5 67.2 0.9 0.028Years postmenopause 22.2 1.0 22.0 0.9 23.5 1.3 0.569Hysterectomy 15 14 19 0.467Previous estrogen therapy 24 27 22 0.644Calcium intake (mg/day) 704 73 589 54 580 52 0.262Family history of osteoporosis 19 15 18 0.183Current smoker 8 14 7 0.135Alcohol use (3 drinks/week) 16 7 6 0.022BMI (kg/m3) 25.3 0.55 24.8 0.61 26.2 0.70 0.311

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hydroxyvitamin D and 1,25-dihydroxyvitamin D did notchange with treatment.

The effects on serum lipids are given in Table 4. As com-pared with the CON group, serum total cholesterol and LDLcholesterol decreased significantly in both treatment groupsand the LDL cholesterol/HDL cholesterol ratio also de-creased significantly in both treatment groups. The HDL cho-

lesterol and triglyceride levels were not significantly altered.

The occurrences of prevalent and incident fractures aregiven in Table 5. For vertebral fractures, there were nosignificant differences among groups using the 15% cutofffracture definition. However, using a 30% cutoff definition,there was a dose-related reduction in vertebral fracture forthe RLX groups which was significantly different fromCON (p 0.047). There were no differences or trends for

differences among groups for nonvertebral fractures.

TABLE 2. BASELINE VALUES AND GROUP CHANGES FROM BASELINE (MEAN SE) AT 6 MONTHS AND 12 MONTHS FOR BMD ATVARIOUS SCANNING SITES

Variables

Treatment group (mean SE)

CON RLX60 RLX120

Total hip (g/cm2) baseline 0.67 (0.002) 0.64 (0.010) 0.69 (0.01)6 months change 0.001 (0.003) 0.002 (0.003) 0.004 (0.002)

% change 0.42 (0.48) 0.43 (0.48) 0.55 (0.48)p* NS NS

12 months change 0.004 (0.003) 0.006 (0.004) 0.004 (0.003)% change 0.71 (0.48) 0.95 (0.62) 0.47 (0.48)

p* 0.027 NSAP lumbar spine baseline 0.77 (0.02) 0.75 (0.02) 0.81 (0.02)

(g/cm2) 6 months change 0.002 (0.004) 0.01 (0.003) 0.02 (0.004)% change 0.33 (0.50) 1.25 (0.47) 1.89 (0.52)

p* NS 0.02512 months change 0.01 (0.004) 0.01 (0.004) 0.02 (0.004)

% change 0.96 (0.55) 1.78 (0.57) 2.07 (0.52)p* NS NS

Lateral lumbar spine baseline 0.54 (0.01) 0.52 (0.01) 0.56 (0.01)(g/cm2) 6 months change 0.003 (0.004) 0.01 (0.004) 0.004 (0.004)

% change 0.78 (0.89) 2.16 (0.81) 0.52 (0.78)p* NS NS


p* NS NSTotal body bone mineral baseline 0.93 (0.01) 0.91 (0.01) 0.95 (0.01)

(g) 6 months change 0.004 (0.005) 0.004 (0.005) 0.004 (0.003)% change 0.35 (0.55) 0.37 (0.51) 0.41 (0.32)

p* NS NS12 months change 0.007 (0.004) 0.002 (0.005) 0.002 (0.004)

% change 0.64 (0.45) 0.11 (0.53) 0.23 (0.43)

p* NS NSRadius distal 1/3 baseline 0.54 (0.01) 0.52 (0.01) 0.56 (0.01)

(g/cm) 6 months change 0.009 (0.002) 0.003 (0.002) 0.002 (0.002)% change 1.63 (0.30) 0.59 (0.32) 0.25 (0.40)

p* 0.031 0.00512 months change 0.009 (0.002) 0.01 (0.002) 0.01 (0.002)

% change 1.75 (0.35) 1.05 (0.34) 0.92 (0.38)p* NS NS

Radius ultradistal baseline 0.32 (0.01) 0.30 (0.01) 0.33 (0.01)(g/cm) 6 months change 0.007 (0.002) 0.002 (0.002) 0.002 (0.002)

% change 1.80 (0.51) 0.14 (0.71) 0.33 (0.60)p* NS NS

12 months change 0.01 (0.002) 0.001 (0.002) 0.002 (0.002)

% change 2.70 (0.56) 0.22 (0.71) 0.19 (0.63)p* 0.002 0.007

* For significance of difference from CON group, using % change. NS, not significant; AP, anteroposterior.

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Adverse events

Of 124 minor symptoms or signs occurring in individualpatients, there were significant differences over CON in thepatients receiving raloxifene only in the higher occurrenceof arthralgia (p 0.027) and dizziness (p 0.024). Theonly significant physical finding was a 6 mm Hg decrease insystolic blood pressure in the two groups receiving ralox-

ifene (p 0.028 overall). None of the patients who re-ported dizziness were found to be hypotensive.

Eight patients discontinued the study because of adverseevents. None of these adverse events were thought to bedrug related, and there was no significant difference be-tween groups in the number of these adverse events.

DISCUSSION

These data clearly demonstrate that at the tissue level,raloxifene has estrogen-like activities in bone. Comparedwith controls, there were significant decreases in serum

bone-specific ALP and serum osteocalcin, markers for bone

formation, and urinary excretion of CTx, a marker of boneresorption, indicating that raloxifene was effective in de-

creasing overall bone turnover. There was also a substantial

decrease in these values in the control group itself, suggest-

ing that the 750 mg/day of calcium supplement received by

all patients also reduced bone turnover. The decreases over

controls in these markers was somewhat less than the de-

creases in serum osteocalcin and serum bone-specific ALP

and in urine hydroxyproline that we previously reported in

patients with postmenopausal osteoporosis receiving 0.1mg/day of 17-estradiol by transdermal patches.(11) The

patients in that trial, however, did not receive calcium

supplementation as did those in the present trial. The de-

creases in biochemical markers of bone turnover were sim-

ilar to those in the 2-month treatment trial reported by

Draper et al.(8) for normal early postmenopausal women.

Our results are also quite comparable to those of Delmas et

al. who evaluated the effect of three dosages of RLX inyounger, healthy postmenopausal women.(12)

We also were able to document an effect on retardation

of the rate of bone loss in the raloxifene treatment groups

TABLE 3. MEAN ( SE) AND RANGE FOR BASELINE VALUES AND GROUP CHANGES FROM BASELINE AT 6 AND 12 MONTHS FORBIOCHEMICAL MARKERS OF BONE TURNOVER AND FOR SERUM PTH

Serum variables

Treatment group

CON RLX60 RLX120

Bone-specific ALP (g/l) baseline 14.6 (0.94) 14.2 (0.92) 13.8 (1.0)6 months change 2.10 (0.69) 4.14 (0.76) 3.97 (0.74)

% change 10.9 (4.7) 24.5 (5.7) 24.1 (5.5)p 0.015 0.027


p* 0.006 0.026Osteocalcin (g/l) baseline 24.5 (1.4) 22.3 (1.2) 24.0 (1.4)


p 0.001 0.00112 months change 3.62 (1.1) 7.91 (0.83) 7.31 (0.86)

% change 12.4 (4.3) 33.1 (3.0) 29.4 (3.0)p* 0.001 0.005

CTx/Cr Ratio (g/mmol) baseline 349 (32) 251 (21) 295 (28)6 months change 63.6 (26) 94.9 (20) 130 (22)

% change 11.4 (8.3) 31.0 (7.6) 39.1 (5.9)p* 0.037 0.005

12 months change 91.5 (28) 114 (19) 127 (18)% change 11.0 (9.8) 35.9 (8.0) 41.8 (4.6)

p* 0.009 0.026PTH (pg/ml) baseline 3.70 (0.16) 3.48 (0.19) 3.16 (0.14)


p* 0.002 0.00112 months change 0.49 (0.16) 0.10 (0.17) 0.28 (0.17)

% change 9.70 (4.3) 10.8 (5.5) 15.3 (5.9)

p* 0.006 0.001

* For signifiance of difference from CON group, using ranked % change.



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as compared with the control group. This reached signifi-cance for the measurements at the total hip for the 60

mg/day dosage and at the distal and ultradistal radius forboth dosages. However, there was a clear trend towardlower rates of loss at all measurement sites except that forthe lateral lumbar spine, a site which has a relatively poorprecision because of the large amount of soft tissue in thebeam pathway.(13) This suggests that there was a general-ized effect of treatment on preventing skeletal bone loss butthat we may not have had the statistical power to assessrates of change over controls in the remaining sites in whichthe 1-year changes over controls ranged from 0.5% to 1.1%.Even at the measurement sites at which there were signif-icant differences, the 1-year changes over controls whichranged from 1.7% to 2.9% in the present study were less

than those in our previous study with transdermal estro-

gen,(11) which ranged from 1.2% to 5.5%. At least part ofthis difference may have been due to the cotreatment with

calcium and the somewhat lesser degree of osteoporosis inthe present study. However, it is also possible that the effectof raloxifene on bone loss may more resemble that oftamoxifen, in which bone mass is maintained over the initialyears of treatment,(4) than that of estrogen, in which thereis a 1012% increase in bone density during the initial 23years of treatment followed by a further maintenance atthat level,(11) even in elderly women.(14,15) To resolve thisissue, more data are needed in a larger number of patientsundergoing parallel treatment limbs with control, ralox-ifene, and estrogen.

Our findings also indicate that raloxifene HCl is a safeand efficacious treatment for women with established post-

menopausal osteoporosis. In keeping with studies in exper-

TABLE 4. BASELINE VALUES AND GROUP CHANGES FROM BASELINE AT 6 AND 12 MONTHS (MEAN SE) FOR SERUM LIPID

Serum variables

Treatment group

CON RLX60 RLX120

Total cholesterol (mmol/l) baseline 5.99 (0.12) 6.05 (0.16) 5.81 (0.14)6 months change 0.14 (0.10) 0.41 (0.10) 0.54 (0.14)

% change 1.92 (1.6) 6.10 (1.6) 8.37 (2.3)p* 0.049 0.009


p* 0.042 NSHDL cholesterol (mmol/L) baseline 1.46 (0.05) 1.48 (0.05) 1.47 (0.04)



% change 0.84 (1.8) 4.65 (2.1) 2.21 (1.8)p* NS NS

LDL cholesterol (mmol/l) baseline 3.89 (0.12) 3.91 (0.15) 3.71 (0.12)6 months change 0.11 (0.09) 0.39 (0.09) 0.45 (0.11)

% change 2.31 (2.1) 8.76 (2.4) 10.7p* 0.019 0.004


p* 0.009 NSTriglycerides (mmol/l) baseline 1.47 (0.11) 1.45 (0.11) 1.36 (0.10)



% change 0.40 (4.6) 1.48 (7.4) 4.57 (5.6)p* NS NS

LDL cholesterol/HDL baseline 2.78 (0.12) 2.78 (0.14) 2.64 (0.12)cholesterol ratio 6 months change 0.06 (0.07) 0.26 (0.09) 0.35 (0.08

% change 1.42 (2.4) 8.96 (3.0) 11.4 (2.9)p* 0.005 0.001


p* 0.001 0.032

*For significance of difference from CON group, using ranked % change. NS, not significant.

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imental animals showing that raloxifene acts as an anties-trogen on the breast and endometrium, there were nosignificant differences over controls in symptoms of masto-dynia or abnormalities detected by mammography or inmenstrual bleeding or differences in endometrial thickness.None of the patients had evidence of thromboembolism.

The meaning, if any, of the small reported increase in minorsymptoms of arthralgia and dizziness in the patients receiv-ing raloxifene is unclear. However, even if such symptomsdo occur, we feel they would not be a deterrent to the futureuse of the drug. We were particularly interested to find thatvasomotor symptoms (perspiration or hot flushes) were nomore prevalent in the two treatment groups than in con-trols. Flushing is not uncommon with tamoxifen treatment,and occurred in 22% of patients treated with raloxifene 600mg/day versus 11% in controls in the previous study byDraper et al.(8) Thus, vasomotor symptoms with raloxifenetreatment appear to be dose related.

Although we recorded the effect of raloxifene on fracture

rate as a secondary variable, our study was not designed tohave enough statistical power to detect differences in frac-ture rate. We found no differences over controls in thecombined groups receiving raloxifene in the occurrence ofvertebral fractures as defined by the requirement for a 15%decrease in vertebral height. However, when only moresevere fractures were assessed using the 30% cutoff defini-tion, the dose-dependent reduction was significant. Basedon the new concept that both increases in bone mass anddecreases in bone turnover lead to decreases in fracturerate,(16) the reduction of bone turnover that we observed inthe raloxifene therapy groups would be expected to lead toa decrease in vertebral fracture rate. Larger studies will be

needed to corroborate this prediction.

As in the short-term study by Draper et al.(8) we foundthat raloxifene significantly decreased the serum LDL cho-lesterol/HDL cholesterol ratio, a major predictor of coro-nary heart disease.(17) There were also reductions in serumtotal cholesterol and serum LDL cholesterol in the 60mg/day treatment group and trends for raloxifene treatment

to be associated with decreases in all lipid fractions exceptfor serum HDL cholesterol which did not change. Similarresults were also reported in the ovariectomized rat model.(7)

Although these changes in serum lipids suggest that raloxifenetherapy will protect against the occurrence of coronary arteryischemic events, it also may have other beneficial preventiveeffects such as direct effects on blood vessels(18) or on arterialblood flow, which have been reported to occur in experimentalanimals treated with estrogen.(19)

Estrogen replacement is considered to be the treatmentof choice for most women with osteoporosis.(20) Physiolog-ical replacement dosages administered to postmenopausalosteoporotic women normalize high levels of bone turn-

over(21)

and also reduce the vertebral fracture rate.(14,22)

Estrogen deficiency is considered to be one of the maincauses of the disease, and ERT in postmenopausal womenoffers many physiological benefits including a decreasedincidence of coronary ischemic events,(23) improved mem-ory, concentration, and attention span.(24) However, manypostmenopausal women are unwilling to accept renewedmenstruation, breakthrough bleeding, mastodynia, fluid re-tention, or premenstrual syndrome-like symptoms which mayoccur with long-term HRT. Most importantly, there are recentdata that support strongly the contention that long-term es-trogen therapy is associated with an increased risk for breastcancer.(25) Even though this is still a subject of debate,(26) the

issue has had wide coverage in the mass media, and a general

TABLE 5. SUMMARY OF PREVALENT FRACTURES AT BASELINE AND INCIDENT FRACTURES OVER 1 YEAR IN THETREATMENT GROUP

Treatment group

CON RLX60 RLX120

Number of patients* 45 43 45Vertebral fractures (15% cutoff definition)

median prevalent fractures 4.5 5.5 5number of patients with 1 incident fracture 18 21 20number of incident fractures 39 38 48mean incident fracture rate (fractures/year) 0.72 0.71 0.89

Vertebral fractures (30% cutoff definition)median prevalent fractures 1 1 1number of incident fractures 13 8 4mean incident fracture rate (fractures/year) 0.25 0.14 0.08

Nonvertebral fracturesnumber of baseline nonvertebral fractures 40 40 29number of atraumatic incident nonvertebral fractures 3 0 3number of baseline hip fractures 4 2 1

number of incident hip fractures 0 0 1number of baseline radius fractures 13 16 7number of incident radius fractures 0 0 0

* Number of patients 143 because 10 patients discontinued the study and did not have a follow-up spine X-ray at 1 year.



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concern about this issue is probably the main reason that manypostmenopausal women find ERT unacceptable. Thus, thereis a need for a compound that would maintain the favorableeffects of estrogen but would avoid its unfavorable effects.

In conclusion, we found that raloxifene treatment ofwomen with established osteoporosis was safe and welltolerated. Like estrogen, it acted to reduce bone turnover

and prevent bone mineral loss and had beneficial lipideffects. But unlike estrogen, it did not stimulate the endo-metrium, thus preventing uterine bleeding, and was free ofbreast-stimulating effects. Thus, it appears to be a promis-ing new form of treatment for women with establishedpostmenopausal osteoporosis, particularly for women whoare unable or unwilling to take estrogen.

ACKNOWLEDGMENTS

We are indebted to Ginny Wong, R.N., Nancy Gilliland,R.N., and Joan Muhs, R.N. for their expert management of

the study patients. Dr. Michael Draper, Lilly ResearchLaboratories, was extremely helpful in the design and pros-ecution of this clinical trial. This work was supported by agrant from Eli Lilly and Company.

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Address reprint requests to:Edward G. Lufkin, M.D.

Mayo Clinic

Division of Endocrinology and Metabolism,

West 18-A

200 First Street SW

Rochester, MN 55905 U.S.A.

Received in original form October 24, 1997; in revised form June

22, 1998; accepted July 2, 1998.

1754 LUFKIN ET AL.

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Raloxifene n Osteoporosis