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POSTMENOPAUSAL OSTEOPOROSIS
early postmenopausal women. International
Study Group. Bone 1999; 24: 517–23
15. Cooper C, Stakkestad JA, Radowicki S, et al.
Matrix delivery transdermal 17beta-estradiol for
the prevention of bone loss in postmenopausal
women. The International Study Group. Osteo-
poros Int 1999; 9: 358–66
16. Weiss SR, Ellman H, Dolker M. A randomized
controlled trial of four doses of transdermal estra-
diol for preventing postmenopausal bone loss.
Transdermal Estradiol Investigator Group. Obstet
Gynecol 1999; 94: 330–6
17. Notelovitz M, John VA, Good WR. Effectiveness
of Alora estradiol matrix transdermal delivery
system in improving lumbar bone mineral
density in healthy, postmenopausal women.
Menopause 2002; 9: 343–53
18. Ettinger B, Ensrud KE, Wallace R. Effects of
ultralow-dose transdermal estradiol on bone min-
eral density: a randomized clinical trial. Obstet
Gynecol 2004; 104: 443–51
19. Thijssen JH. Overview on the effects of pro-
gestins on bone. Maturitas 2003; 46: S77–87
20. Isoniemi H, Appelberg J, Nilsson CG, et al.
Transdermal oestrogen therapy protects post-
menopausal liver transplant women from osteo-
porosis. A 2-year follow-up study. J Hepatol 2001;
34: 299–305
21. Rubinacci A, Peruzzi E, Modena AB, et al. Effect
of low-dose transdermal E2/NETA on the reduc-
tion of postmenopausal bone loss in women.
Menopause 2003; 10: 241–9
274
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Progestogens and bone
D. W. Sturdee
31
INTRODUCTION
In considering the many factors which influence
bone remodeling, it is inevitable that most dis-
cussions will concentrate on the influence of
estrogen, and the recent developments in non-
hormonal therapies such as bisphosphonates and
strontium-containing products. However, the
hormonal influence on bone is not limited to
estrogens alone. Other steroids such as androgens
and corticosteroids are important, as well as
hormones such as growth hormone, thyroid
hormones, parathyroid hormone, calcitonin and
1,25-dihydroxyvitamin D
1
. In addition, there is
an increasing body of evidence that progesterone
and progestogens can influence bone metabolism.
PROGESTERONE RECEPTORS AND
BONE
The expression of both estrogen receptors (ERs)
and progesterone receptors (PRs) in normal
human osteoblast-like cells has been well docu-
mented
1–3
, and several lines of evidence support
a role for steroid hormones in regulating the
expression and function of matrix proteins and
metalloproteinases involved in bone remodeling
and resorption
4
.
Progesterone may also influence bone remod-
eling by acting as a ligand for the glucocorticoid
receptor. Glucocorticoids have been implicated
in the process of bone loss through their ability
to block 1,25(OH)
2
-vitamin D-induced osteocal-
cin synthesis
5
and to prevent the attachment of
osteoblasts to matrix proteins. Progesterone may
antagonize these effects, resulting in a reduction
of the glucocorticoid-induced bone loss
6
.
There are two progesterone receptors, a and
b, both of which are promoted by estradiol. PRb
is a strong activator of target genes, but PRa acts
as a dominant repressor of PRb. Therefore, the
response of individual cells depends on the ratio
of PRa/PRb. Estrogen receptor
α is the predom-
inant inducer of PRa
7,8
.
CLINICAL EVIDENCE
The clinical evidence of the effect of progesto-
gens on bone is found in fertile women taking
contraception, premenopausal women receiving
gonadotropin-releasing hormone (GnRH) ther-
apy with additional progestogen or combinations
of estrogen and progestogen, and post-
menopausal women taking hormone therapy.
Progestogen-only contraception
Breast-feeding mothers experience a reversible
reduction in bone mineral density (BMD) due to
lowered estrogen levels associated with ovulation
suppression. In a study of 31 women followed for
1 year postpartum, breast-feeding together with
barrier methods of contraception resulted in a
mean reduction in spinal BMD of 4.9 ± 1.5% by
6 months, whereas those who were breast-
feeding and using oral progestogen-only contra-
ception had a spinal BMD at 1 year that was
2.95 ± 0.75% higher than immediately postpar-
tum
9
. This study concluded that the small
amount of progestogen in the progesterone-only
pill would appear to protect against the loss of
bone resulting from breast-feeding.
Levonorgestrel subdermal implants (Nor-
plant
®
) are used widely, and especially in China,
for contraception. In a prospective randomized
clinical trial involving 61 women of child-
bearing age studied over 1 year in China, a small
but significant increase in lumbar spine (2.4%)
275
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POSTMENOPAUSAL OSTEOPOROSIS
and proximal femur (3.34%) BMD (p < 0.01)
was reported
10
. Similar findings were reported by
Naessen and colleagues
11
in a study comparing
the differential effects of depot medroxyproges-
terone acetate (DMPA) and subdermal levo-
norgestrel implants over 6 months. While there
was a significant increase in forearm BMD of
2.94% (p = 0.006) in women who were pre-
scribed levonorgestrel, there was no effect on
bone density during treatment with DMPA at
standard clinical doses for contraception. Other
recent studies with DMPA have raised concern
about bone loss due to the suppression of ovula-
tion. A 2-year study of 38 premenopausal
women using DMPA, and randomized to receive
in addition either conjugated equine estrogens
(CEE) 0.625 mg daily or a matching placebo,
showed a significant decline in lumbar spine
BMD in the placebo group, but no change in
those receiving CEE
12
(Figure 1). A further study
of adolescent females using DMPA compared
with combined oral contraception and a control
group has also reported a significant loss of bone,
compared with controls, which was not seen in
those on combined oral contraceptive pills
13
(Table 1) . Such data have prompted the Com-
mittee on Safety of Medicines (CSM) in the UK
to send advice to prescribers that the prolonged
use of DMPA in adolescents may impair the
attainment of peak bone mass. Although BMD
starts to recover when DMPA is stopped in adult
women, and at the menopause the bone density
of users may be no different from that of women
who have never used DMPA
14,15
, the extent of
recovery in adolescents is not known. In women
with significant life-style and/or medical risk fac-
tors for osteoporosis, the CSM has advised that
other methods of contraception should be con-
sidered
16
. When DMPA was used together with
GnRH therapy for women with symptomatic
fibroids prior to surgery, DMPA had no effect on
the bone loss associated with GnRH
17
. However,
when norethisterone is used in conjunction with
GnRH, the bone loss is prevented
18
(Figure 2).
Postmenopausal hormone therapy
In symptomatic postmenopausal women,
progestogens such as norethisterone
19
and mege-
strol
20
have been shown to give some relief from
vasomotor symptoms. In addition, several stud-
ies have also demonstrated that norethisterone
will prevent bone loss in postmenopausal
women. A study of 43 symptomatic post-
menopausal women in Glasgow, of whom 20
received norethisterone 5 mg twice daily for 2
0
98
100
102
104
081218 24
Time (months)
% Change in lumbar spine BMD
Conjugated estrogens
Placebo
p
< 0.01
p
< 0.002
Figure 1 Lumbar spine bone mineral density (BMD) in 38 premenopausal women using depot
medroxyprogesterone acetate (MPA) and randomized also to receive either conjugated equine estrogens
0.625 mg daily or matching placebo. Difference between the groups was 3.2% at 18 months and 3.5% at 24
months. Reproduced from reference 12, with permission
276
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years and the others had placebo, showed a
marked difference in the metacarpal bone min-
eral content (p < 0.001)
21
(Figure 3). Horowitz
and colleagues
22
also demonstrated that
norethisterone 5 mg per day in women with
postmenopausal osteoporosis prevents further
bone loss by decreasing bone turnover, increasing
serum parathyroid hormone and having an
independent effect on vitamin D and calcium
absorption. However, progestogens are not com-
monly given alone to postmenopausal women,
but are included in combination therapy pre-
dominantly for protection of the endometrium.
Combinations of norethisterone with ethinyl-
estradiol have produced a dose-related significant
increase in BMD that was not present with
277
Table 1 Lumbar vertebral bone mineral density in adolescent females using depot medroxyprogesterone
acetate (DMPA) or combined oral contraception (COC) compared with controls
13
6 months 12 months 18 months
n Change (%) n Change (%) n Change (%)
DMPA 36 –0.249
*
27 –1.59
**
24 –2.91
***
COC 27 1.170 16 2.35 11 3.82
Control 14 2.768 10 2.45 5 0.73
*p < 0.014; **p = 0.001; ***p < 0.001
PROGESTOGENS AND BONE
100
90
Mainly cortical bone
BMC prox. (%)
100
90
Mainly trabecular bone
BMC dist. (%)
100
90
TBBM
BMD spine
0
6
12
Months Months
Change (%) Change (%)
Change (%)
Variation in changes during
1 year in control group
(mean ± 1 average SEM)
Treatment period
Treatment with nafarelin plus NET
Treatment with nafarelin alone
100
90
0
6
12
Change (%)
Figure 2 Changes in bone mass during treatment and after withdrawal of treatment with nafarelin plus
norethisterone (NET) 1.2 mg daily and nafarelin alone. BMC, bone mineral content; TBBM, total body bone mineral;
BMD, bone mineral density.
*
p< 0.05;
**
p< 0.01 (vs. baseline). Reproduced from reference 18, with permission
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Thus, in postmenopausal women, the combi-
nation of norethisterone with estrogen does seem
to have an additive effect on preventing bone loss,
whereas such an effect has not been demonstrated
with any other progestogen. Norethisterone is
one of the few progestogens to demonstrate some
estrogenic activity, with bioconversion to estro-
genic compounds that activate both ER
α and
ER
β
32,33
in addition to other progesterone-like
activities. This may be the main reason why it has
a different effect on bone metabolism compared
with the other progestogens.
In a review on the apparent lack of effect of
progestogens on bone, Lindsay
34
stated that ‘evi-
dence so far suggests that when used alone at nor-
mally prescribed dosages, progestogens have nei-
ther direct effect on osteoporosis nor an additive
effect when used as a component of HRT. Positive
effects of HRT on bone seen in postmenopausal
women are more likely a direct result of the estro-
gen component’. Furthermore, although proges-
terone receptors are evident in bone tissue and on
osteoblasts in particular, it is not clear whether the
currently available progestogens are able to bind
specifically to the PR isoforms PRa and PRb
35
.
None of the data presented above have demon-
strated any effects on bone remodeling from a
progestogenic action mediated through PR.
CONCLUSIONS
Progestogens may have more relevance to bone
metabolism in premenopausal than in post-
menopausal women. DMPA is associated with
loss of bone, especially in adolescent girls, due to
suppression of ovarian function. In addition, the
bone loss associated with breast-feeding may be
prevented by progestogen-only oral contracep-
tive preparations. In the postmenopausal
woman, micronized progesterone, medroxyprog-
esterone acetate, megestrol, dydrogesterone and
trimegestone do not prevent postmenopausal
bone loss. Norethisterone acetate, however, may
have an independent positive effect as well as
additional benefits when combined with estro-
gen in postmenopausal women, although this
may be due more to some estrogenic activity
rather than a pure progestogenic action.
278
Active
Placebo
061218 24
38
39
40
41
42
43
44
45
BMC (%)
Months
p
< 0.001
Figure 3 Metacarpal bone mineral content (BMC)
in women receiving norethisterone 5 mg twice daily
compared with placebo over 2 years. Reproduced
from reference 21, with permission
POSTMENOPAUSAL OSTEOPOROSIS
unopposed ethinylestradiol
23
. A similar effect has
been demonstrated when norethisterone is com-
bined with estradiol, showing a positive effect on
postmenopausal bone metabolism and an
increase in bone mass more than expected and
more than with treatment with alendronate
24
(Figure 4). Conversely, the addition of oral
medroxyprogesterone acetate or oral micronized
progesterone to CEE does not appear to give any
additional benefit to the bone-sparing effects of
CEE alone
25
. Other progestogens, such as dydro-
gesterone
26
, that have been studied either alone
or in combination with estrogen have not shown
any obvious additive effect on bone loss. The new
progestogen trimegestone, when given alone or
in combination with 17
β-estradiol, also does not
inhibit the effect of estrogen in maintaining bone
mass, while at the same time completely block-
ing its proliferative effect on the endometrium
27
.
Progesterone cream has been advocated as a
natural replacement for postmenopausal women
who are lacking progesterone, but the claims for
an effect on osteoporosis
28
have not been sub-
stantiated. Several studies have failed to demon-
strate any clinically significant increase in serum
progesterone following the application of proges-
terone cream, and, in a 12-week study of women
using transdermal progesterone cream 32 mg
daily, there were no detectable changes in clinical
symptoms or bone mineral activity markers
29–31
.
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279
6
4
2
0
–2
–5
Change from baseline (%)
2 mg E
2
+ 1 mg
NETA
1
mg E
2
+ 0.5 mg
NETA
1
mg E
2
+ 0.25 mg
NETA
1
mg E
2
0.5 mg E
2
0.25 mg E
2
Placebo
Figure 4 Effects of oral estradiol ± norethisterone acetate (E
2
± NETA) at different doses on spinal bone
mineral density after 26 months. Reproduced from reference 24, with permission
PROGESTOGENS AND BONE
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norgestrel-releasing subdermal contraceptive
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13. Lara-Torre E, Edwards CP, Perlman S, Hertweck
SB. Bone mineral density in adolescent females
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atr Adolesc Gynecol 2004; 17: 17–21
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progesterone acetate. Br Med J 1994; 308: 247–8
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medroxyprogesterone acetate contraception. Am
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Medroxyprogesterone acetate with Zoladex™ for
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density and patient acceptability. Hum Reprod
1997; 12: 436–40
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years. The main interest was to see whether low-
ering the dose before stopping hormone replace-
ment therapy (HRT) would have any effects on
the parameters studied, e.g. bone. This phase
was completed in early 2004. There will still be
one follow-up visit, with BMD and other meas-
urements, approximately 1 year after discontin-
uation of study treatments.
The aim of bone marker determinations was
to elucidate whether a single baseline measure-
ment of serum intact N-terminal propeptide of
type I procollagen (PINP) can reliably predict
short-term skeletal treatment response 12
months after treatment start, using lumbar spine
BMD as reference.
DESIGN AND METHODS
The study, starting in 1994 as a parallel-group,
double-blind, dose-finding trial with 419 women
randomized to six HRT regimens, containing 1
2
V combined with 2.5 or 5 mg of
MPA (Indivina
®
; Orion Pharma, Finland), was
continued after the 2-year double-blind period,
first as a single-blind and later as an open study,
in order to gather more efficacy – especially
regarding bone – and safety information.
Three of the dose options were registered for
marketing in 1999. The unregistered dose com-
bination of 2 mg E
2
V with 2.5 mg MPA was no
longer manufactured, and therefore women
Effect of different dose options of continuous
combined hormone therapy on bone and bone
marker N-terminal propeptide of type I
procollagen: results from a long-term study
in Finnish postmenopausal women
J. Heikkinen and J. Haapalahti
32
281
INTRODUCTION
Estrogen–progestogen therapy has long been the
treatment of choice for the prevention of osteo-
porosis, and the Women’s Health Initiative study
results confirmed its efficacy in preventing frac-
tures in a randomized setting
1
. However, the
results of the same study raised concern about
the safety of long-term hormone replacement
therapies in postmenopausal women, and turned
the focus toward shorter-term therapies
2
.
In 2000, we published the 4-year bone min-
eral density (BMD) results from an ongoing clin-
ical trial involving 419 women randomized to
four different estradiol valerate (E
2
V) and
medroxyprogesterone acetate (MPA) dose
options in six treatment regimens, as in two
treatment groups the E
2
V component was dou-
bled after the initial 6 months while, in the
remaining four groups, the dose combinations
remained the same throughout the study
3
. The
four dose combinations were: 1 mg E
2
V+
2.5 mg MPA (1 + 2.5); 1 mg E
2
V+5mg MPA
(1 + 5); 2 mg E
2
V+2.5 mg MPA (2 + 2.5) and
2 mg E
2
V+5mg MPA (2 + 5).
After 7 treatment years, the long-term safety
results were reported
4
. When all women had
completed the 8th year, the focus was turned
toward the lowest dose regimen for the rest of
the period, with switching all women still in the
study (n = 232) to this dose option for the last 6
months of the total active study period of 9
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receiving this dose option had to discontinue the
study after the completion of 7 years. Results for
this dose option are not reported here.
Bone mineral density measurements
BMD was measured at the lumbar spine (L2–L4)
and the hip (femoral neck, Ward’s triangle,
trochanter) by dual-energy X-ray absorptiometry
at baseline, 6 months, 12 months and annually
thereafter. The final measurement will be made
when the women have been without study treat-
ment for approximately 1 year.
Bone marker (PINP)
determinations
For PINP determination, serum samples from a
subgroup of 44 women on the lowest dose option
of 1 + 2.5 were taken at baseline and at 12
months. Further PINP determinations were
performed at the end of the active study period (9
years). The last PINP determination will be made
1 year after treatment stop. PINP is measured
using commercially available reagents (Orion
Diagnostica UniQ
®
PINP radioimmunoassay).
In order to assess the power of the initial
PINP level to predict treatment response at the
12-month time-point on bone metabolism, the
baseline PINP results from 44 patients were
divided into quartiles and, after combining quar-
tile 1 with 2 and 3 with 4, two groups were
formed: group A (low bone turnover) with base-
line PINP < 40
µg/l (n = 22), and group B (high
bone turnover) with basal PINP > 40
µg/l
(n = 22).
RESULTS
The main baseline characteristics of the study
population at baseline are given in Table 1.
Bone mineral density
After 4 years of treatment, with 296 women
completing this period, the mean increases from
baseline in femoral and lumbar BMD were simi-
lar in the 1-mg and 2-mg E
2
V groups, but at all
sites the increase was most pronounced in the
groups where the estrogen dose had been dou-
bled 6 months after treatment start. The
increases were more pronounced in women with
Table 1 Baseline characteristics of women in study
Group
1–2 + 5 2+ 5 1 + 2.5 1 +5
(n = 70) (n = 70) (n = 69) (n = 70)
Age (years, mean ± SD) 56.2± 1.8 56.1 ± 2.0 56.0 ± 2.0 56.3 ± 2.1
Age at menopause (years, mean ± SD) 48.9 ± 2.6 49.0 ± 3.2 49.4 ±2.2 48.8 ± 3.0
Body mass index (BMI) (kg/m
2
, mean ± SD) 25.6 ± 3.16 25.4 ± 2.9 25.2 ± 2.8 25.4 ± 2.8
Previous HRT (n (%)) 38 (54.3%) 32 (45.7%) 38 (55.1%) 36 (51.4%)
Smokers (%) 12.9 7.1 14.5 14.3
Women (%) with lumbar spine (L2–L4) femoral neck
normal BMD 43 57
osteopenia 45 40
osteoporosis 12 3
SD, standard deviation; HRT, hormone replacement therapy; BMD, bone mineral density
282
POSTMENOPAUSAL OSTEOPOROSIS
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low bone mass at baseline. The MPA dose did
not seem to have any effect on bone (Figures 1
and 2).
In all groups, BMD increased more rapidly
during the first 3–4 years, with mean annual
increases of 1–2%. Then the increases began to
level out, but still a slightly increasing trend
could be seen at the lumbar spine (Figure 3).
At the femoral neck, BMD values started to
decrease slightly around 72–84 months from the
peak increases of 3.5–4% (Figure 4).
At the end of the active study period, the
mean increases from baseline at the lumbar spine
ranged between 8% (group 1 + 5) and 10% (2+
5), and at the femoral neck between 1% (1 + 5)
and 2% (2 + 5) (Figure 5). Based on preliminary
analyses, no effect of the dose reduction for the
last 6 months could yet be established.
Using the cut-off point of ± 2%, over 85% of
women who completed the 9-year period had
gained BMD of more than 2% during the study,
and in approximately 5% no relevant change in
BMD was observed. In less than 5% of women,
a decrease of more than 2% could be seen at the
end of the study. By the end of the active 9-year
study period, the proportion of women with low
bone mass (osteopenia or osteoporosis) had
decreased, compared with baseline (Table 1),
with the majority of women now having normal
BMD values (Figure 6).
Bone marker PINP
By the 6th treatment month, the PINP values
determined from 44 women receiving the lowest
dose option showed a significant decrease from
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8
6
4
2
0
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8
6
4
2
0
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6
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Time (months)
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6
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Time (months)
Mean change in BMD from baseline (%)
Lumbar spine
all women
Femoral neck
all women
Lumbar spine
T-score below –1
Femoral neck
T-score below –1
1–2/2.5
1–2/5
2/2.5
2/5
1/2.5
1/5
Figure 1 Mean changes (%) in lumbar and femoral bone mineral density (BMD) after 4 years of treatment.
All women and women with low bone mass at baseline (BMD T-score below -1). Figure reproduced with
permission from Osteoporosis International
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EFFECT OF CONTINUOUS COMBINED HRT ON BONE AND BONE MARKER PINP
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