Breast Cancer Research and Treatment (2005) 93: 277–287
Springer 2005

DOI 10.1007/s10549-005-5701-x

Report

Bone mineral density and lipid changes during 5 years of follow-up in a study
of prevention of breast cancer with toremifene in healthy, high-risk pre- and
post-menopausal women

R. Erkkola1, L. Mattila2, T. Powles3, J. Heikkinen4, B. Toivola2, P. Korhonen2, and

M. Mustonen2
1
Department of Obstetrics and Gynaecology, Turku University Central Hospital, Turku, Finland; 2Orion Corporation
Orion Pharma, Espoo, Finland; 3The Royal Marsden Hospital, Breast Unit Downs Road, Sutton, UK; 4Osteoporosis
Clinic, Oulu Deaconess Institute, Oulu, Finland

Key words: anti-oestrogen, bone mineral density, chemoprevention, cholesterol, early termination, toremifene

Summary
A double-blind, randomised, placebo-controlled pilot study was initiated to evaluate the feasibility of chemopre-
vention with toremifene 60 mg/day in healthy women at high risk for breast cancer. Enrolment in the study was
terminated earlier than planned because of slow patient accrual, although 13% of patients continued for 5 years.
The revised efficacy outcomes were change in bone mineral density (BMD) from baseline at four skeletal sites, plus
effects on serum lipids. In premenopausal women there was a trend for sustained increase in BMD during tore-
mifene therapy after year 1 in lumbar spine. In postmenopausal women, toremifene had little or no effect on BMD
trends. Levels of total and low-density lipoprotein (LDL) cholesterol were largely unchanged from baseline in
premenopausal women treated with toremifene but were often slightly lower than in the placebo group during
follow-up. Total and LDL cholesterol levels declined slightly from baseline in the postmenopausal women and were,
at several points during the first 3 years, significantly lower than in the corresponding placebo group (p < 0.01). We
conclude that: (a) assessment of toremifene 60 mg/day in chemoprevention will require further clinical trials; (b)
toremifene 60 mg/day has no substantive negative effects on BMD in pre- or postmenopausal women and may exert
a minor favourable influence (in particular, the effects of toremifene 60 mg/day on BMD in premenopausal women
may make the drug an attractive alternative to tamoxifen 20 mg/day for that patient subset); (c) lipid effects of
toremifene 60 mg/day are, at minimum, neutral and may be modestly favourable for reducing cardiovascular risk.

Introduction The original objective of this study was to evaluate the

The selective oestrogen receptor modulator (SERM)
toremifene is pharmacologically related to tamoxifen
and has been shown to be clinically comparable to
tamoxifen for prolonging remission and increasing sur-
vival in patients with oestrogen receptor-positive or
receptor-status-unknown breast cancer [1–5].
Tamoxifen has shown potential in the primary pre-
vention of breast cancer in categories of receptor-positive
high-risk patients [6, 7], although its general use for that
purpose is not currently considered a viable strategy [6, 8].
Reasoning by analogy from the comparable mechanisms
of action and clinical effects of toremifene and tamoxifen
in other studies in breast cancer suggests that toremifene
may have value as a chemopreventive agent.
We undertook a randomised, double-blind, placebo-
controlled, parallel-group, multicentre feasibility (Phase
I) study at centres in Finland and the UK to investigate
the effects of toremifene 60 mg daily in 259 healthy pre-
postmenopausal women at high risk for breast cancer.
acceptability, acute toxicity, compliance and safety of
toremifene 60 mg/day treatment, in comparison with
placebo, for the chemoprevention of breast cancer in
women at high risk of developing breast cancer. Because
of slow accrual and results from the pre-planned 1-year
interim analysis, patient recruitment was ended earlier
than scheduled and the follow-up was continued using
the revised efficacy outcomes of change in bone mineral
density (BMD) from baseline at four skeletal sites and
effects on serum lipids.
Study schedule
The study schedule specified a baseline assessment with
subsequent follow-up visits every 6 months for 5 years,
plus a follow-up visit 1 year after discontinuation of the
study. An additional visit could be scheduled for
3 months after initiation of the treatment, at the dis-
cretion of study investigators.
278 R Erkkola et al.
Originally the study included three parallel groups:
toremifene 60 mg/day, tamoxifen 20 mg/day and pla-
cebo. Enrolment in the tamoxifen group ceased on 27
January 1999 because of slow recruitment arising from
difficulties in obtaining satisfactory informed consent
for that therapy.
Patients and eligibility criteria
Healthy non-pregnant women aged 40–70 years with a
life expectancy of >10 years were eligible to participate
in the study if they satisfied the following inclusion
conditions.
• Family history of breast cancer (one first-degree
relative [mother, sister, daughter] plus at least one
other relative [mother, sister, daughter, maternal
aunt or grandmother])
• Mother, sister or daughter with diagnosis of breast
cancer at age 45 years or less, or bilateral breast
cancer
• Use of barrier contraceptive if potential for pregnancy
• Psychologically and medically suitable for long-term
follow-up
• Written, informed consent from each patient.
Participation in the study was not subject to, or
limited by, particular menstrual status. A patient was
considered premenopausal if she was menstruating and/
or her oestrogen, luteinising hormone, and follicle-
stimulating hormone levels in serum were within the
hospital laboratory reference range.
Exclusion criteria included: previous exposure to
study medications, raloxifene or any related anti-oes-
trogen or SERM; previous history of invasive malig-
nancy (except ductal carcinoma in situ or basalioma) or
thromboembolic disease; clinical or radiological evi-
dence of carcinoma; endometrial thickening >8 mm in
postmenopausal patients identified at baseline by
transvaginal ultrasound; concomitant medication with
significant effect on BMD, serum lipids or calcium and
phosphate metabolism; any pre-existing metabolic or
endocrine abnormality considered to have clinically
significant effects on BMD or calcium and phosphate
metabolism; steroidal hormone therapy (including, but
not limited to, contraception or hormone replacement
therapy [HRT]) during the immediately preceding
6 months; significant liver, renal or cardiac dysfunction;
expected inability to comply with the requirements of
the protocol.
Randomisation procedure and medication
Patients satisfying all the eligibility criteria were rando-
mised to toremifene 60 mg/day, tamoxifen 20 mg/day,
or placebo. All treatments were given orally. The ran-
domisation was carried out at the Department of Bio-
statistics and Data Management, Orion Pharma, Espoo,
Finland. The number of patients randomised into the
three study groups was balanced within each partici-
pating study site and further stratified according to the
menopausal status of the individuals.
All study medications were manufactured, packed
and labelled under conditions that complied with the
requirements of Good Manufacturing Practice for
Medicinal Products (Commission of the European
Communities and Pharmaceutical Inspection Conven-
tion) by Orion Pharma, Turku, Finland. Patient com-
pliance was monitored through self-reported tablet
consumption.
Ethics
The study was conducted in accordance with the current
valid revision of the Declaration of Helsinki of the
World Medical Assembly, in conformity with the pro-
tocol Guideline for Good Clinical Practice (ICH/135/95)
and in conformity with regulations concerning clinical
trials issued by local medical authorities, including
the National Agency for Medicines in Finland (no. 6/93,
1/01) and the UK Medicines Control Agency.
The study protocol and all relevant amendments were
reviewed and approved by local Ethics Committees.
Written informed consent was obtained from every
participant after a presentation of verbal and written
information about the objectives and procedures of the
study and the possible risks and benefits involved. Par-
ticipants were free to withdraw from the study at any
time without giving any reason for doing so.
Efficacy variables
The original objective of this study was to evaluate the
acceptability, acute toxicity, compliance and safety of
toremifene 60 mg/day treatment, in comparison with
placebo, for the chemoprevention of breast cancer in
women at high risk of developing breast cancer. The
original efficacy variables were revised before the pre-
planned 1-year interim analysis. The revised primary
efficacy variable was the per cent change in BMD at the
lumbar spine (L2–L4) and proximal femur neck from
baseline to 12, 24, 36, 48 and 60 months. Secondary
variables comprised the per cent change in BMD at
Ward’s triangle and the major trochanter from baseline
to 12, 24, 36, 48 and 60 months, plus absolute changes
from baseline in serum total cholesterol, low-density
lipoprotein (LDL) cholesterol, high-density lipoprotein
(HDL) cholesterol and triglycerides.
BMD at the spine (L2–L4 region) and all three
nominated territories of the hip was measured
using dual-energy X-ray absorptiometry at baseline and
at 12-month intervals. All BMD measurements at each
participating centre were performed by the same, skilled
staff member using the same equipment throughout the
study.

Serum samples of blood for the determination of
total cholesterol, LDL cholesterol, HDL cholesterol and
triglyceride concentrations were drawn at baseline, and
at the 3-, 6- and 12-month visits, and every 6 months
thereafter or at premature discontinuation (when pos-
sible). The ratio of HDL: total cholesterol was calcu-
lated at the Royal Mardsen Hospital, Department of
Biochemistry, London, for UK centres, and at a single
site in Finland (Medix Diacor Laboratory Services,
Espoo), according to standard laboratory practice.
Transvaginal ultrasound measurements and endo-
metrial biopsies were taken from postmenopausal
individuals at baseline and at the 12-, 24-, 36-, 48- and
60-month visits. Maximal endometrial thickness (dou-
ble-layer) was measured in the longitudinal plane.
Mammography was performed at baseline and annually
thereafter, and supplemented with ultrasound investi-
gation if abnormalities were detected.
Clinical assessment of acute toxicity was performed
at each follow-up visit. Baseline physical examinations
and laboratory assessments were repeated at the 3-, 6-
and 12-month visits, and thereafter at intervals of
6 months. Adverse events (AEs) were coded according
to the MedDRA dictionary.
Statistical methods
Statistical analyses were performed under the supervi-
sion of the Department of Biostatistics and Data Man-
agement of Orion Pharma, Espoo, Finland. The
statistical package SAS release v8.2 was used for all
calculations.
Statistical testing of the revised primary endpoints
used an analysis of variance model with the effects:
treatment group (placebo vs. toremifene); country (UK
vs. Finland); time (12, 24, 36 and 60 months), and
menopausal status (pre- versus postmenopausal). Inter-
actions for treatment group by time, treatment group by
menopausal status, and treatment group by menopausal
status and time were also examined. The baseline value of
the relevant BMD was used as a covariate in this model.
Hypothesis testing was performed using a two-sided
significance level of 0.029. This significance level was
chosen to maintain an overall nominal significance level
of 0.05 after one interim analysis and the final analysis.
For the analyses of secondary endpoints a two-sided 5%
significance level and 95% confidence intervals were used.
Analysis of data from patients randomised to tamox-
ifen was confined to safety and tolerability reporting.
Results
Patient characteristics
The first participant was randomised on 11 November
1996 and the last on 25 November 2002. Details of
BMD and lipid changes during toremifene therapy 279
participating centres (two in the UK and four in
Finland) are provided in Appendix 1.
In all, 259 patients were enrolled, of whom 116 each
were randomised to toremifene and placebo, and 27 to
tamoxifen. Patients’ dispositions are summarised in
Figure 1. The main reason for discontinuing study
medication prematurely was the decision to terminate
the trial ahead of schedule because of slow recruitment
and a breach of one of the protocol-specified stopping
rules in the subgroup of premenopausal women (see
section ‘Bone Mineral Density’, below). The distribution
of duration of exposure to study medication arising
from that decision is summarised in Table 1. AEs were
the next largest cause of premature discontinuations
(toremifene n = 35, placebo n = 15, tamoxifen n = 7).
Some 75% of patients randomised to toremifene and
85% of those randomised to placebo completed at least
12 months of treatment (Table 1). Mean follow-up was
35.4 months.
All subjects were Caucasian. Other salient demo-
graphic details are shown in Table 2. The treatment
groups were well matched for baseline characteristics
such as prevalence of concomitant diseases.
Bone mineral density
The results presented were derived from the intent-to-
treat (ITT) cohort.
Lumbar spine
For the subset of premenopausal women, the difference
in mean change in BMD from baseline to 12 months
between the toremifene and placebo groups was statis-
tically significant (p = 0.0214) and satisfied the condi-
tions of one of the study stopping rules. At all
subsequent evaluations, premenopausal patients treated
with toremifene had net increases in mean BMD which
were at all times comparable in magnitude to, and not
statistically different from, the trends in the placebo
group (Figure 2a).
Mean changes in lumbar BMD from baseline in
postmenopausal women were small at all times up to
48 months in both study groups (Figure 2b). There were
no statistically significant differences between toremifene
and placebo in postmenopausal women at any time
during the study.
Mean values of lumbar BMD during the study are
summarised in Table 3.
Femoral neck
Trends in mean BMD are illustrated in Figure 3a for
premenopausal women and in Figure 3b for postmen-
opausal women. There were no statistically significant
differences between toremifene and placebo at any time
during the study for mean change in femoral neck BMD
from baseline. In the premenopausal women, the end-of-
study mean BMD increases at the femoral neck were
15.55% in the toremifene group and 16.10% in the
280 R Erkkola et al.

N=259
Subjects allocated
and entered

Tamoxifen Toremifene Placebo

N=27 N=116 N=116

Never started Never started

study treatment. study treatment.
N=1 N=2

ITT ITT ITT

N=27 N=115 N=114

Prem ature Prem ature Prem ature

Com pleted Com pleted Com pleted
discontinuation discontinuation discontinuation
N=15 N=13 N=14
N=12 N=103 N=102

AE/SAE 7 AE/SAE 35 AE/SAE 15

lost to follow-up 3 lost to follow-up 2 lost to follow-up 4
non-com pliance 0 non-com pliance 6 non-com pliance 5
protocol violation 7 protocol violation 7
protocol violation 0
prem ature term ination of study prem ature term ination of study
prem ature term ination of study
N=53 N=71
N=2

Figure 1. Disposition of patients, showing derivation of the intent-to-treat (ITT) cohort. ‘Premature discontinuations’ includes patients who
never started treatment. AE, adverse event; SAE, serious adverse event.

placebo group. In the postmenopausal women, the Table 2. Demographic. characteristics of patients receiving toremifene
corresponding changes were 20.57 and 16.42%. or placebo (intent to treat cohort)

Variable Toremifene Placebo

(mean ± SD) (n = 115) (n = 114)
Trochanter and Ward’s triangle
In the premenopausal women, mean BMD at the tro- Age (years) 52.9 ± 8.4 53.8 ± 9.1
chanter decreased by 0.98% in the toremifene group Height (cm) 162.7 ± 5.1 162.5 ± 5.8
after 12 months of treatment compared with an increase Weight (kg) 70.3 ± 14.7 70.9 ± 12.2
of 3.28% in the placebo group (Figure 4a). This differ- BMI (kg/m2) 26.6 ± 5.4 26.9 ± 4.5
ential in favour of placebo persisted throughout the Menopause status
Premenopausal 36 38
Postmenopausal 79 76
Prior hormone replacement therapy
Table 1. Patient exposure to study medication (intent to treat cohort)
Yes 54 53
Time Toremifene Tamoxifen Placebo No 61 61
(months) (n = 115*) (n = 27) (n = 114**) Smoking
Yes 23 16
£ 12 27 5 14
No 92 97
£ 24 11 4 7
No data 0 1
£ 36 24 0 21
Relatives with breast cancer
£ 48 28 2 38
Yes 115 114
£ 60 16 9 26
No 0 0
>60 8 7 5
Missing data 1 0 3 Relatives with other cancer
Yes 69 67
*116 patients randomised; 1 received no treatment. No 46 47
**116 patients randomised; 2 received no treatment.
 BMD and lipid changes during toremifene therapy 281

Table 3. In-study changes in bone mineral density at the lumbar spine

(a) (premenopausal)
16 (g/cm3) and patient numbers at yearly units
Toremifene
14 Placebo
Treatment n Mean SD
12

10 Premenopausal
8
Baseline Toremifene 35 1.11 0.12
Placebo 37 1.11 0.15
6 p=0.0214
12 months Toremifene 26 1.08 0.13
4
Placebo 27 1.13 0.16
2
24 months Toremifene 25 1.13 0.17
0 Placebo 21 1.14 0.18
-2 12 months 24 months 36 months 48 months 60 months 36 months Toremifene 18 1.15 0.18
Placebo 19 1.20 0.20
(b) (premenopausal) 48 months Toremifene 14 1.20 0.15
16
Toremifene Placebo 16 1.22 0.23
14 Placebo 60 months Toremifene 14 1.22 0.14
12
Placebo 11 1.24 0.18
10 Postmenopausal
8 Baseline Toremifene 79 0.93 0.14
6 Placebo 76 0.92 0.16
4
12 months Toremifene 59 0.94 0.15
Placebo 69 0.92 0.17
2
24 months Toremifene 51 0.93 0.14
0
Placebo 67 0.92 0.16
-2 12 months 24 months 36 months 48 months 60 months
36 months Toremifene 33 0.94 0.14
Figure 2. Mean percentage change in lumbar spine bone mineral den- Placebo 43 0.94 0.20
sity from baseline in (a) pre- and (b) postmenopausal patients who 48 months Toremifene 7 0.97 0.27
received either toremifene or placebo. For patient numbers see Table 3.
Placebo 15 0.99 0.19
60 months Toremifene 1 1.24 N/A
study and was statistically significant at 12 and Placebo 4 1.12 0.03
36 months (p  0.015). Thereafter, the numerical supe-
riority of placebo was still apparent but no longer sta-
tistically significant. 18
(a) (premenopausal)
In postmenopausal women, there was almost no 16 Toremifene
change in mean BMD in either group until the fourth 14
Placebo

year of the study (Figure 4b), with no indication of a

12
statistically significant inter-group difference at any time
10
during the trial.
8
Trends in mean BMD in Ward’s triangle are illus-
trated in Figure 5a for premenopausal women and in 6

Figure 5b for postmenopausal participants. 4

2
Lipid profile 0
12 months 24 months 36 months 48 months 60 months
Baseline lipid and lipoprotein values are shown in
Table 4. In-study trends are reported for the ITT co- 25
(b) (postmenopausal)
hort. Assignment to study medication was the only
20 Toremifene
factor shown in analysis of variance to significantly
Placebo
influence in-study changes in total or lipoprotein cho- 15
lesterol. Triglyceride responses were not associated with
treatment assignment in analysis of variance. 10

Total cholesterol 5

In-study changes in total cholesterol are illustrated in

0
Figure 6. Throughout the study and regardless of
alterations in cholesterol levels relative to baseline, levels -5 12 months 24 months 36 months 48 months 60 months
in the toremifene group tracked lower than the corre- Figure 3. Mean percentage change in femoral neck bone mineral
sponding level in the placebo group. With the exception density from baseline in (a) pre- and (b) postmenopausal patients who
of the 12-month data (net reduction of 0.45 mmol/l with received either toremifene or placebo. For patient numbers see Table 3.
282 R Erkkola et al.

(a) (premenopausal) toremifene versus placebo; p = 0.035), no significant

16
intergroup differences were noted in the cohort of pre-
14 Toremifene p=0.0143 menopausal women during the study.
12 Placebo In the subset of postmenopausal women the reduc-
10 tions in total cholesterol seen in the toremifene group
8 were statistically significantly different from the changes
6 p=0.0153
in the placebo group at every annual assessment up to
and including 36 months (but marginally non-significant
4
at 30 months, p  0.06) (Figure 6). No significant
2
intergroup differences were evident in the postmeno-
0 pausal women from month 42 to the end of the study.
-2 12 months 24 months 36 months 48 months 60 months
LDL cholesterol
(b) (postmenopausal)
20 Figure 7 depicts in-study changes in LDL cholesterol.
18
Toremifene
Trends in LDL cholesterol were generally significantly
16
Placebo lower with toremifene than in the placebo group during
14
the first 36 months of the trial, in both pre- and post-
12
menopausal women, with no significant differences
10
thereafter.
8
6
4
HDL cholesterol
2
In-study changes in HDL cholesterol were small in both
0 study groups and were not regarded as clinically rele-
-2 12 months 24 months 36 months 48 months 60 months vant. There were, with isolated exceptions in favour of
Figure 4. Mean percentage change in trochanter bone mineral density
toremifene, no significant intergroup differences and no
from baseline in (a) pre- and (b) postmenopausal patients who received substantial differences between pre- and postmeno-
either toremifene or placebo. For patient numbers see Table 3. pausal women.

Triglycerides
Net changes in mean triglycerides were general small
(i.e. not exceeding ± 0.5 mmol/l) except in postmeno-
(a) (premenopausal) pausal women at ‡54 months (when N £ 4). There
30 p=0.018
were no significant differences between groups.
Toremifene
25 Placebo
Safety and tolerability
20
One or more AE was recorded in 103 (89.6%) patients in
15 the toremifene group and 100 (87.7%) patients in the
placebo group. Seventy-seven of the 103 AEs recorded in
10
the toremifene-treated patients and 47 of the 100 recorded
5 in the placebo group were regarded as probably or pos-
sibly related to the use of study medication. (These cal-
0 culations were based on the selection from each patient of
12 months 24 months 36 months 48 months 60 months
the event with the most probable causality.)
(b) (postmenopausal) The most commonly occurring AEs were weight
35 increase (toremifene 31.3% of patients, placebo 17.5%),
30 Toremifene breast tenderness (12.2% versus 24.6%), hot flushes
Placebo (21.7% versus 10.5%), irregular menstruation (17.4%
25
versus 14.0%), weight decrease (13.0% versus 17.5%)
20 and menopausal symptoms (20.9% versus 7.9%).
15 Thirty-five patients discontinued toremifene and 15
10
stopped using placebo because of AEs.
Adverse drug reactions (AEs considered probably or
5
possibly related to study medication, or not assessable)
0 were recorded in 79 (68.7%) patients treated with toremi-
-5 12 months 24 months 36 months 48 months 60 months fene and 54 (47.4%) of those who received placebo. At least
Figure 5. Mean percentage change in Ward’s triangle bone mineral
one adverse drug reaction was recorded in 23/27 patients
density from baseline in (a) pre- and (b) postmenopausal patients who in the tamoxifen group. A summary of most frequently
received either toremifene or placebo. For patient numbers see Table 3. recorded adverse drug reactions appears in Table 5.
 BMD and lipid changes during toremifene therapy 283

Table 4. Baseline lipids and lipoprotein values in the intent to treat cohort

Lipid parameter Toremifene (n = 115) Placebo (n = 114)

Mean SD Mean SD

Total cholesterol Premenopausal 5.09 0.96 5.05 1.12

Postmenopausal 6.22 1.00 6.34 1.09
Low-density lipoprotein cholesterol Premenopausal 3.11 0.84 3.01 1.07
Postmenopausal 3.93 1.00 4.03 0.98
High-density lipoprotein cholesterol Premenopausal 1.37 0.39 1.32 0.39
Postmenopausal 1.66 0.36 1.70 0.48
Triglycerides Premenopausal 1.67 1.93 1.40 0.97
Postmenopausal 1.41 0.73 1.57 1.74

A total of 59 serious AEs (SAEs) were reported in 45 Clinical laboratory observations revealed minor
individuals (17.6% of all randomised patients). Of these, changes considered to be of no clinical relevance.
23 were associated with toremifene use, 33 with placebo Serial mammography disclosed isolated cases of be-
and 3 with tamoxifen. Fifty-three of these SAEs were nign calcification or fibrocystic changes but no instances
considered not to be related to the use of study treat- of newly emergent breast cancer. The incidence of new
ment (19 for toremifene, 31 for placebo and 3 for breast abnormalities (excluding baseline data) among
tamoxifen). Details of the remaining 6 SAEs (4 with women taking tamoxifen was about twice that among
toremifene; 2 with placebo) are provided in Table 6. women taking toremifene (26% versus 11%, p = 0.053
Fisher’s exact test). Toremifene thus had an abnormality
rate similar to that of placebo (11% versus 15%). The
2
A b so lu te c h n a ge fro m b as e line (m m o l/L )

findings of clinical breast examinations were consistent

1. 5
with the mammography data.
1

0. 5

0
Discussion
-0.5

-1 This study was initiated as an investigation of the po-

-1.5 tential of toremifene in the chemoprevention in women
-2 considered to be at high risk of developing breast cancer
-2.5 by virtue of their family history. These original goals
12months 24 months 36 months 48 months 60 months
were subsequently modified in response to a combination
Toremefine (Pre) Placebo (Pre) Toremifene (Post) Placebo (Post)
of clinical and logistic factors, namely continued slow
Figure 6. Mean absolute change in total cholesterol from baseline in recruitment and the demonstration of a statistically sig-
pre- (Pre) and postmenopausal (Post) patients who received either
toremifene or placebo; p £ 0.0178 for toremifene versus placebo at 12
nificant intergroup difference in change from baseline of
and 24 months in postmenopausal women and p = 0.0065 at mean lumbar BMD in premenopausal women at
36 months. 12 months. As a result of these circumstances and the
responses to them our research provides no insight for or
against the use of toremifene as a chemopreventive agent
2
Absolute chnage from baseline (mmol/L)

in women with a risk profile conforming to that origi-

1.5
nally planned for this study. An evaluation of toremifene
1 for this application will require further clinical trials.
0.5 Early termination of the study and slow patient
0 enrolment meant that our trial had limited statistical
-0.5
power, especially in the later years. This limitation needs
-1
to be borne in mind when considering the results of our
revised efficacy assessment. Nevertheless, the opportu-
-1.5
nity to continue monitoring BMD beyond the period
-2 12months 24 months 36 months 48 months 60 months when the initial relative decline in mean BMD in the
Toremefine (Pre) Placebo (Pre) Toremifene (Post) Placebo (Post) lumbar spine in premenopausal women mandated stop-
Figure 7. Mean absolute change in low-density lipoprotein cholesterol ping the study revealed that this trend was reversed by
from baseline in pre- (Pre) and postmenopausal (Post) patients who 24 months (Figure 2a) and that thereafter toremifene use
received either toremifene or placebo; p £ 0.0123 for toremifene was not associated with any adverse effect on BMD in
versus placebo at 12 and 36 months in premenopausal women;
that territory. The recovery of mean BMD at a point in
p < 0.001; for toremifene versus placebo at 12, 24 and 36 months in
postmenopausal women. follow-up when our study retained reasonable numbers
284 R Erkkola et al.

of patients encourages us to believe that this is a genuine
effect and to conclude that longer-term use of toremifene
60 mg/day is unlikely to be associated with substantive
adverse effects on BMD if used for up to 5 years. This
conclusion also appears to be valid for both pre- and
postmenopausal women, despite the qualitative varia-
tions in response in these two subsets of patients.
The effects of toremifene on BMD at the lumbar
spine and trochanter of premenopausal women were
significantly inferior to those of placebo at 12 and
36 months, respectively. The first of these findings
mandated the premature termination of the trial.
A bone-wasting effect of tamoxifen has also been
reported in premenopausal women [9, 10]. These data
suggest, prima facie, that both tamoxifen and toremifene
cause a reduction in BMD in premenopausal women,
presumably through anti-oestrogenic actions. However,
this apparent similarity of outcome conceals a possibly
important difference in experience with these two drugs.
The effects of tamoxifen on BMD in premenopausal
women were characterised by a significant decline in
BMD during anti-oestrogen therapy, whereas BMD in
the placebo group remained stable [10]. In our experi-
ence, by contrast, the inferiority of toremifene was the
product of 0.54% mean reduction from baseline in the
toremifene-treated patients compared with 3.32% in-
crease in BMD in the placebo group. The mean BMD
response with placebo during the first year of our
investigation compares favourably with the response to
various forms of osteoporosis therapy in postmeno-
pausal women [11, 12], including some experiences with
Table 5. Most frequently reported adverse drug reactions
Toremifene
(n = 115)
n (%)
Weight increase 22 (19.1)
Hot flushes 20 (17.4)
Menopausal symptoms 21 (18.3)
Weight decrease 11 (9.6)
Irregular menstruation 12 (10.4)
combination HRT [13, 14] and raloxifene [15].
A marked placebo response, rather than a substantive
decline in BMD with toremifene, is thus the major factor
contributing to the overall statistical difference. The
statistically significant intergroup differences in tro-
chanter mean BMD change at 1 and 3 years and at
Ward’s triangle in the late years of the study (when
patient numbers were small) may be explained in a
similar way.
From a clinical rather than a statistical perspective we
consider it more informative to examine trends in mean
BMD change throughout the study, while endeavouring
to give due consideration to the decline in patient num-
bers in the later course of the study. Figures 2–5a con-
sistently exhibit a trend for increases in BMD with
increasing duration of toremifene therapy. We therefore
conclude that our data are compatible with the inter-
pretation that premenopausal women continue to accrue
BMD during toremifene treatment for up to at least
5 years, albeit for the most part at a lesser rate than in the
placebo group. We have made no investigation of the
possible impact of hormonal contraceptives on these
results, beyond confirming that none of the exclusions
for protocol violations were due to the use of such
agents. It is not known whether contraceptive agents
affect BMD, but it has been reported that HRT may lead
to acceleration of bone loss [16, 17]. A similar effect of
hormonal contraceptives (assuming unbalanced use of
these agents in the toremifene and placebo groups) might
have contributed to difference in the Year 1 BMD
responses at the lumbar spine.
The BMD response seen in premenopausal women
treated with toremifene may be attributed to the net
effect of the natural response to endogenous oestrogens
versus an anti-oestrogenic effect of toremifene that was
Placebo of lesser potency than is seen with tamoxifen 20 mg/day
(n = 114) [10]. We do not believe it plausible that the increase in
BMD seen with continued treatment with toremifene is
n (%) due to some kind of time-dependent emergence of pro-
14 (12.3)
oestrogenic pharmacology. In particular, examination
9 (7.9)
of mean BMD data in Figures 2–5a and 2–5b provides,
6 (5.3)
in our opinion, no reason to think that recovery of
10 (8.8)
BMD in premenopausal women with continued therapy
8 (7.0)
was attributable to unmonitored transitions from pre- to
postmenopausal status.

Table 6. Description of serious adverse events (SAEs) considered related to use of study medication

Group Background information Duration of treatment SAE Continuation of the study

before SAE

Toremifene Liver function tests increased 2 months Icterus; Liver function tests increased Discontinued
Toremifene Endometrial thickening 32 months Endometrial disorder (normal findings) Discontinued
Toremifene Not reported 38 months Drug overdose; Depression Continued
Toremifene Endometrial hypertrophy 57 months Persistently thickened endometrium Discontinued
Placebo Headache in left side 4 months Cerebrovascular disorder Continued
Placebo Intermenstrual bleeding 42 months Intermenstrual bleeding; Bilateral Continued
ovarian cysts

The effect of toremifene on BMD in the premeno-
pausal participants in our study contrasts sufficiently with
the previously reported data for tamoxifen 20 mg/day
[10] for us to conjecture that toremifene 60 mg/day may
be preferred to tamoxifen 20 mg/day in premenopausal
women, especially those identified as being at risk for the
development of osteopenia or osteoporosis. This sugges-
tion requires further clinical evaluation, however, and
even if proven would probably not supersede the use of
potent antiresorptive therapies in that subset of patients.
In postmenopausal women, toremifene was associ-
ated with preservation or modest accrual of BMD at all
four of the skeletal sites monitored. We consider the
sharp increase in BMD in these patients in the later
years of the trial to be a statistical artefact attributable
to the very low numbers of postmenopausal women
contributing to the analysis at those times (e.g. toremi-
fene n = 7 at 48 months, n = 1 at 60 months; placebo
n = 15 and 4, respectively; Table 3). This comparison of
BMD data across sites (Figures 2–5b) provides little if
any indication of site-specific differences in the effect of
toremifene on BMD during this study.
We have not analysed our BMD data from post-
menopausal women according to HRT. Some
researchers [16–18] but not others [19] have reported
that prior use of HRT (followed by discontinuation) is
associated with accelerated bone loss in postmenopausal
women. Similarly, we have not investigated any impact
from the use of agents such as antiresorptive bis-
phosphonates. These limitations notwithstanding, how-
ever, we consider that these data indicate, at a minimum,
that toremifene 60 mg/day has no obvious bone-
depleting effect in postmenopausal women. This con-
clusion, which is broadly in conformity with studies of
tamoxifen [20–22], is supported by the observation that
BMD in women randomised to toremifene was either
stable or slightly increased during the first 3 years of the
study (when patient numbers were relatively large),
whereas in other studies a spontaneous reduction in
BMD has been seen in postmenopausal women not
using HRT [19].
Toremifene had modest but essentially favourable
effects on the lipoprotein profile of the patients who
participated in this study. Among postmenopausal wo-
men, the trends in total and LDL cholesterol might
confer some reduction in cardiovascular risk if sustained
long-term. It would, however, be premature to interpret
our data as a clear promise of such a benefit. Longer-
term clinical outcome data on this subject for tamoxifen,
which is assumed to exert its effects on lipids through
similar mechanisms [21, 23–28], are not consistent or
conclusive. Moreover, to the extent that these effects are
attributable to oestrogenic actions, experience with
HRT in postmenopausal women emphasises the need
for caution in the interpretation of surrogate endpoints
[29–32]. Overall, however, these data reveal no obvious
adverse effect of toremifene 60 mg/day on lipid/lipo-
protein risk factors for cardiovascular disease in either
pre- or postmenopausal women.
BMD and lipid changes during toremifene therapy 285
Tamoxifen was associated with about twice the
incidence of new breast abnormalities when compared
to toremifene and placebo. Interestingly, the percentage
of patients reporting breast-related pain or tenderness in
the toremifene group was about half that recorded with
either tamoxifen or placebo (data not shown). Such
breast-related events may be indicative of premalignant
change, as may oestrogen-independent increases in
breast density [33, 34].
In conclusion, this final analysis of data from a
5-year feasibility study of toremifene (60 mg/day) in
the prevention of breast cancer in high-risk women has
provided indications that use of this anti-oestrogen
therapy is associated with either preservation or an
increase in BMD during medium-term use and with
changes to the lipoprotein profile consistent with a
possible modest reduction in cardiovascular risk. The
overall safety and tolerability profile of toremifene was
acceptable and is consistent with earlier experience.
The fact that there were fewer breast events in the
toremifene group is outwardly supportive of the notion
that toremifene may have chemopreventive effects in
this high-risk patient group, but a separate, adequately
powered study is necessary to substantiate any such
claim.
Acknowledgements
We express our appreciation to all patients who volun-
teered to take part into this study. We also like to thank
the whole study group, Mr Juha Ellmen (Orion Pharma,
Finland) and Ms Päivi Nevala (Orion Pharma, Finland)
for their invaluable knowledge and expertise on breast
cancer field, and their help in reviewing this manuscript,
and Mr Peter Hughes and Dr Gillian Gummer of
Hughes associates, Oxford, UK, for assistance with
manuscript preparation.
Appendix I. Summary details of study centres and
principal investigators
Finland:
Department of Obstetrics and Gynaecology, Turku
University Central Hospital, Turku (Risto Erkkola,
M.D.)
Bulevardin lääkäriasema, Helsinki (Erkki Hirvonen,
M.D., Ph.D.) Oulu Deaconess Institute, Osteoporosis
Clinic, Oulu & Kemin Röntgen, Kemi (Jorma Heikki-
nen, M.D.)
UK:
The Royal Marsden Hospital, Breast Unit, Downs
Road, Sutton, Surrey SM2PT & Royal Marsden Hos-
pital NHS Trust, Fulham Road, London SW3 6JJ
(Trevor Powles, B.Sc., Ph.D., FRCP and Ian Smith,
B.Sc., M.D., FRCP)
286 R Erkkola et al.
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Address for offprints and correspondence: Mika Mustonen, Orion
Corporation Orion Pharma, Orionintie 1, PO Box 65, FI-02101 Espoo,
Finland; Tel.: +358104294804; Fax: +358104293055; E-mail:
mika.mustonen@orionpharma.com