Beerthuizen 2000

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Human Reproduction vol.15 no.1 pp.118–122, 2000
Bone mineral density during long-term use of the
progestagen contraceptive implant Implanon® compared
to a non-hormonal method of contraception
Rob Beerthuizen1, Agaath van Beek2,5, et al., 1998). Oestrogen deficiency leads to bone loss in pre-
menopausal women or into achieving a lower peak bone massRebeca Massai3, Leo Mäkäräinen4,
Joanneke in’t Hout2 and Herjan Coelingh Bennink2 than their age-related peers, who have a normal oestrogen
status. Hypothalamic amenorrhoea in young women is associ-1Streekziekenhuis Koningin Beatrix, Winterswijk, The Netherlands,
ated with low serum 17β-oestradiol concentrations and low2Research and Development, NV Organon, Oss, The Netherlands,
bone mass. In situations where amenorrhoea is induced by3Chilean Institute of Reproductive Medicine, Santiago, Chile and
4Department of Obstetrics and Gynaecology, University of Oulu, medical treatment such as administration of depot medroxypro-
Oulu, Finland gesterone acetate (DMPA), a lowered oestrogen status is also
observed. During use of Implanon®, amenorrhoea occurs in5To whom correspondence should be addressed at: Clinical
Development Department, NV Organon, PO Box 20, 5340 BH Oss, ~20% of women (Croxatto et al., 1999). It is therefore
The Netherlands important to examine the bone mineral density (BMD) of
the women using this implant, together with the oestrogenAn open, prospective, comparative study was done in
concentrations, for possible associations. A randomized designhealthy women, aged between 18 and 40 years, to study
would have been most desirable from a scientific point ofthe effects of long-term etonogestrel treatment on bone
view. However, the contraceptive choice of the women beingmineral density (BMD). The control group used a non-
offered such diverse methods as an implant or an intrauterinehormone-medicated intrauterine device (IUD). The BMD
device (IUD) has to be respected and does not allow ran-was measured using a dual energy X-ray absorptiometry
domization.instrument. Measurements included the lumbar spine (L2–
The study presented here is a prospective, comparative studyL4), the proximal femur (femoral neck, Ward’s triangle,
of a progestagen-only hormonal contraceptive implant and atrochanter) and distal radius. The period of treatment was
non-hormone medicated IUD, for the duration of 2 years.2 years and 44 women in the Implanon® group and 29 in
the IUD group provided data. Groups were comparable at
baseline with respect to age, weight, body mass index, BMD
Materials and methodsand 17β-oestradiol status. Changes from baseline in BMD
In all, 79 women who chose a long-term form of contraception werein the Implanon® group were not essentially different from
informed about the study. Women interested were offered the choicethose in the IUD group. There was no relationship between
between Implanon® and a non-hormone-medicated IUD. Moreover,17β-oestradiol concentrations and changes in BMD in this
women already fitted with an IUD were also allowed to be enrolled.study population. The results of the present study indicate
Permission to carry out the study was obtained from the healththat Implanon® can safely be used in young women who
authorities and the Ethics Committees of the three countries/centres.
have not yet achieved their peak bone mass. All women gave informed consent in writing. The ratio of Implanon®:
Key words: bone mineral density/contraceptive implant/etono- IUD use was chosen to be 1.5:1. Women had to fulfil a set of
gestrel/3-ketodesogestrel/17β-oestradiol inclusion and exclusion criteria. The most important were: age
between 18 and 40 years, good physical and mental health, not
suffering from a condition (present and history) affecting bone
metabolism, not on medication affecting bone metabolism, and a
Introduction weight between 80 and 130% of ideal (Metropolitan Height and
Implanon® is a single-rod implant (NV Organon, Oss, The Weight Tables, 1983). Women with significant scoliosis, hindering
the BMD measurements, were also not enrolled. Present use of �2Netherlands) made of an ethylene vinyl acetate copolymer
units of alcohol per day and smoking �10 cigarettes a day were(EVA) with a core containing 68 mg of etonogestrel (3-
exclusion criteria. Likewise, women engaging in rigorous exercise,ketodesogestrel). The implant has a length of 40 mm and a
such as the marathon or triathlon, were not included. To avoid thediameter of 2 mm and is provided in a sterile disposable
risk of significant baseline differences between treatment groups, weapplicator for subdermal insertion. Contraceptive action is
aimed at a balance in age and weight categories per centre. In thismainly by inhibition of ovulation and lasts for 3 years
way, two important confounders could be taken into account at
(Mäkäräinen et al., 1998). enrolment.
Ovarian oestrogen production is suppressed to early follic- The initial laboratory assessments included measurement of calci-
ular phase concentrations, especially during the first 6 months tonin, parathyroid hormone (PTH), cholesterol, triglycerides and
of use. Upon continued use, oestrogen concentrations show an prolactin. Results had to be within the laboratory reference range, to
increase but, due to the ovulation inhibition also present in allow inclusion into the study. During 4 successive weeks, oestradiol
was measured twice a week, to get an impression of the women’sthe third year, oestrogen lacks the cyclical peaks (Mäkäräinen
118 © European Society of Human Reproduction and Embryology
Bone mineral density during long-term use of Implanon®
Table I. Baseline characteristics of the treatment groups
Implanon® % IUD %
(n � 46) (n � 30)
Age (years)
Mean 30.8 31.4
SD 5.0 4.6
18–20 1 2.2 0
21–25 6 13.0 5 16.7
26–30 12 26.1 7 23.3
31–35 19 41.3 11 36.7
36–40 8 17.4 7 23.3
Height (cm)
Mean 164.9 164.6
SD 6.9 7.8
Body weight (kg)
Mean 63.5 63.8
SD 8.6 7.3 Figure 1. Oestradiol and bone mineral density (L2–L4) at baseline.
BMI (kg/m2)
Mean 23.3 23.5
SD 2.5 2
�20 4 8.7 2 6.7
�20–22 9 19.6 4 13.3
�22–24 15 32.6 11 36.7
�24–26 12 26.1 9 30.0
�26 6 13.0 4 13.3
Pregnancy
0 6 13.0 1 3.3
1 9 19.6 7 23.3
2 15 32.6 11 36.7
3 10 21.7 8 26.7
�3 6 13.0 3 10.0
Parity
0 6 13.0 2 6.7
1 13 28.3 6 20.0
2 17 37.0 16 53.3
3 10 21.7 5 16.7
�3 0 1 3.3
Mean oestradiol (pmol/l) 332.2 312.0
SD 127.4 146.1
Figure 2. Oestradiol (pmol/l) during treatment. Medians areLast contraceptive method
Never used any 0 0 connected. Boxes represent 25 and 75 percentiles, whiskers 5 and
Oral contraceptives 11 23.9 0 95 percentiles. IUD � intrauterine device.
Implants 0 0
Injectables 0 0
reference population]/SD of BMD of reference populationIUD 12 26.1 27 90.0
Condom, diaphragm, 23 50.0 3 10.0 BMD measurements were done in the anteroposterior position at
spermicides the following anatomical sites: lumbar spine (L2–L4), proximal femurOthers 0 0 (femoral neck, Ward’s triangle, trochanter) and the distal radius.
These measurements were performed at baseline, after 6 months ofIUD � intrauterine device; BMI � body mass index.
treatment, after 12 and 24 months. If a woman wished to discontinue
treatment or participation in the study, she was asked to have a ‘final’pre-trial oestrogen status. This schedule was repeated at months 12
BMD measurement done if the previous one had been done �6and 24, or at the moment when the women decided to stop participation
months ago.in the study. At month 6, only one measurement in total was done,
Changes in the z-score of the BMD were compared betweenfor logistic reasons. The three study centres comprised one urban
treatment groups, using analysis of covariance, with centre, age,(Santiago, Chile), one rural (Winterswijk, The Netherlands), and one
weight at baseline, and treatment as covariates.suburban area (Oulu, Finland). The women were of Latin American
The primary parameter was the change in BMD z-score at ‘lastand European ethnicity.
measurement’ i.e. the last measurement done in each subject,eitherThe Lunar DPX software Lunar Corporation, Madison, WI, USA,
at month 24 or upon discontinuation.allowed comparison to different reference populations. For analysis
Scatterplots were used to evaluate the relationship between (changeof our data we used the Lunar company’s female-USA/Europe dataset.
in) oestradiol and (change in) BMD, and the relationship betweenTo apply to our data, average BMD values of the age brackets 20–
weight changes and changes in the BMD. The change in body weight29 and 30–39 years were taken.
was compared between treatment groups with the Cochran–Mantel–BMD measurements (g/cm2) were transformed into standard devi-
Haenszel test, adjusted for centre.ation (SD) scores thus providing z scores (equivalent to T-scores), by
The study had adequate power (α 5%, β 20%) to detect a treatmentmeans of the following equation:
difference in change in z-score of 0.30 between Implanon® users and
IUD users.z � [recorded BMD – mean BMD of (USA/Europe)
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R.Beerthuizen et al.
Table II. Baseline values for bone mineral density per centre
Country Implanon® IUD Overall Referencea
n Mean (SD) n mean (SD) n Mean (SD) Mean (SD)
Lumbar spine Chile 15 1.193 (0.105) 10 1.177 (0.110) 25 1.187 (0.105)
(g/cm2) Finland 15 1.235 (0.118) 10 1.211 (0.075) 25 1.225 (0.102)
The Netherlands 16 1.280 (0.097) 10 1.327 (0.096) 26 1.298 (0.097) 1.198 (0.12)
Femoral neck Chile 15 1.005 (0.111) 10 0.987 (0.065) 25 0.998 (0.094)
(g/cm2) Finland 15 0.993 (0.139) 10 0.971 (0.059) 25 0.984 (0.112)
The Netherlands 16 1.060 (0.126) 10 1.049 (0.130) 26 1.056 (0.125) 0.976 (0.12)
aUSA/European reference population (Lunar Corporation, Madison, Wisconsin, USA).
Table IV. Results from the analysis of covariance for the change fromTable III. Changes over time in bone mineral density
baseline of the BMD z-score at last measurement
Implanon® IUD
(n � 44)* (n � 29)* Site Implanon – IUD Implanon – IUD
Mean Mean Difference 95% CI P-valueMean SD Mean SD
Lumbar spine 0.165 0.037 0.128 (–0.012, 0.268) 0.07Lumbar spine
baseline (g/cm2) 1.234 0.109 1.243 0.111 Femoral neck –0.016 0.069 –0.085 (–0.260, 0.089) 0.33
Ward’s triangle 0.035 –0.032 0.067 (–0.195, 0.329) 0.61z-score (baseline) 0.303 0.909 0.374 0.924
6 months –0.064 0.237 0.071 0.145 Trochanter 0.145 0.100 0.045 (–0.151, 0.241) 0.65
Distal radius* 0.011 0.007 0.004 (–0.003, 0.010) 0.2712 months 0.006 0.335 0.110 0.200
24 months 0.225 0.356 0.038 0.197
last measurement 0.171 0.345 0.031 0.197 CI � confidence interval. Results are adjusted for centre, age and weight at
baseline.Femoral neck
*Distal radius in original measurements (g/cm2), not in z-scoresbaseline (g/cm2) 1.022 0.126 1.003 0.095
z-score (baseline) 0.384 1.049 0.228 0.793
6 months –0.006 0.329 0.051 0.229 Phantom scans was performed by the Bona Fide company, who
12 months –0.031 0.228 0.077 0.290 reported their conclusion in writing.
24 months 0.017 0.399 0.060 0.346
last measurement –0.013 0.389 0.059 0.340
Ward’s triangle Results
baseline (g/cm2) 0.957 0.150 0.942 0.140
Of the 79 women informed about the study, 76 actuallyz-score (baseline) 0.330 1.250 0.212 1.168
6 months –0.027 0.444 0.019 0.367 received treatment. Of these, 46 received the implant and 30
12 months –0.073 0.342 0.089 0.549 an IUD, or were already IUD users. The intention-to-treat
24 months 0.083 0.568 –0.051 0.535
group consisted of 44 implant and 29 IUD users because atlast measurement 0.044 0.546 –0.040 0.529
least one post-baseline measurement was needed. Overall, theTrochanter
baseline (g/cm2) 0.838 0.112 0.816 0.089 two groups were well balanced with respect to age, height,
z-score (baseline) 0.374 0.931 0.195 0.738 weight and body mass index (BMI). Table I presents relevant
6 months –0.001 0.380 0.075 0.271
baseline characteristics of the two treatment groups. The12 months 0.027 0.282 0.101 0.286
24 months 0.206 0.420 0.090 0.346 majority of women had been pregnant in the past and had one
last measurement 0.149 0.445 0.096 0.340 or more children. The contraceptive history showed that
Distal radius particularly the IUD group was homogeneous. Upon entry into
baseline (g/cm2) 0.364 0.047 0.357 0.038 the study, 29 women (out of 30) were already fitted with anz-score (baseline) NA NA
IUD. In 90% of the IUD users, this was also their previous6 months (g/cm2) 0.005 0.016 0.002 0.012
12 months (g/cm2) 0.004 0.012 0.005 0.012 method of contraception, while 24% of the implant users had
24 months (g/cm2) 0.014 0.014 0.008 0.013 been oral contraceptive (OC) users in the past and 26% werelast measurement 0.011 0.016 0.007 0.013
past IUD users. The washout period in case of OC use was 1
*Numbers of subjects vary at the different time points. month. The treatment groups differed with respect to smoking.
NA � not available. In the Implanon® group, 41.3% were smokers compared with
23.3% in the IUD group. Women were not allowed to smoke
The dual energy X-ray absorptiometry (DEXA) instruments (Lunar more than 10 cigarettes a day. Smokers were evenly distributed
Corporation, Madison, WI, USA) at the three different centres were over the three centres.
calibrated at the start of the study and at the end of the study. This
Oestradiol concentrations at baseline were comparablewas done in addition to the routine calibrations done by the staff of
between the two groups (Table I). There was no correlationthe respective centres. In order to have a proper comparison over
between oestradiol concentrations and BMD at baseline (Figuretime, the three study centres should not have shown a difference in
1). Individuals with the lower BMD did not necessarily haveequipment calibration during that period. Calibration was done by
a low oestrogen status and vice versa.Bona Fide (Madison, WI, USA) staff using the European Spine
Phantom, serial number ESP100. Analysis of the European Spine Figure 2 shows the median and 5 and 95 percentiles of the
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Bone mineral density during long-term use of Implanon®
oestradiol serum concentrations over time, based on the average
individual concentrations per timepoint. The single measure-
ment at month 6 was left out. The timepoints usually covered
the mean of eight samples, i.e. 4 consecutive weeks of
measurement. The pattern reveals slightly higher median
oestradiol concentrations in the implant group, when compared
with the IUD group. BMD was generally slightly higher than
that seen in the reference population used by the Lunar
equipment and was highest in women from the rural area of
Winterswijk (The Netherlands) (Table II).
BMD at baseline in g/cm2 and in z-score, followed by
changes over time in z-scores are presented in Table III. BMD
measurements at baseline were comparable between treatment
groups for the anatomical sites of the body measured. For the
Figure 3. Bone mineral density at lumbar spine (L2–L4): z-scoredistal radius absolute changes in g/cm2 are given, since no
during treatment. Medians are connected. Boxes represent 25 and
reference population data were available for the distal radius, 75 percentiles, whiskers 5 and 95 percentiles.
and therefore z-scores could not be provided. The most
important single measurement to be considered was ‘last
measurement’. This measurement included all subjects and
was therefore in no way influenced by discontinuers. In the
implant group ~20% of the subjects discontinued in the 2-year
period, with the highest percentage in The Netherlands (37%)
and the lowest in Chile (13%). Of the IUD users, only 7%
discontinued. At ‘last measurement’ the mean number of days
of exposure to Implanon® was 642 (SD 198.9), whereas the
IUD group participated for 700.3 (SD 157.5) days.
The clinically significant mean decrease of 1 SD (z-score
–1) was not nearly reached at any point. In general, mean
increases from baseline were seen except for ‘femoral neck’
in the Implanon® group and ‘Ward’s triangle’ in the IUD
group, where small decreases were observed. Results from the
Figure 4. Bone mineral density at femoral neck: z-score duringcovariance analysis at thelast measurement indicated that the
treatment. Medians are connected. Boxes represent 25 and 75increase in BMD adjusted for centre, weight and age at
percentiles, whiskers 5 and 95 percentiles.
baseline, was in general slightly greater in the Implanon® than
in the IUD group. This applied to all sites of the body
any significant changes seen in the BMD results were notmeasured, except for the femoral neck, where the BMD in the
attributable to instrument calibration changes.Implanon® group showed a decrease. At none of the anatomical
sites was the difference between the IUD and the Implanon®
group statistically significant. Table IV shows the results from Discussion
the analysis of covariance. The estimated differences between The results of this comparative study show that long-term
the two treatment groups with 95% confidence intervals for treatment with etonogestrel does not adversely affect BMD.
the change from baseline in BMD z-score are presented. Following an early report (Cundy et al., 1991), concern arose
Changes in z-scores over time at L2–L4 and the femoral regarding long-term treatment with progestagen-only agents
neck are shown in Figures 3 and 4. There was no progression and medroxyprogesterone acetate (MPA) in particular. Use of
of ‘bone loss’ in those women with the lowest BMD at baseline MPA is associated to a high degree with amenorrhoea and low
(data not shown). oestradiol concentrations in the young women using it, resulting
During the study period, there was a small mean increase in reduced BMD. Amenorrhoea and oestrogen deprivation are
in weight in the Implanon® group (�1.9 kg), while there was interconnected in the case of hypothalamic amenorrhoea and
no change in weight in the IUD group. In those who had an possibly also in the case of MPA administration. During use
increase in BMD, weight increases as well as decreases of the etonogestrel implant, where amenorrhoea is seen in
occurred. The same applied to those who had a decrease in ~20% of the subjects (Croxatto et al., 1999) this condition is
BMD. Moreover, there was no relationship between oestradiol not interconnected, as was shown previously (Mäkäräinen
at baseline and change in z-score of the BMD, neither was et al., 1998). In this study, amenorrhoea was associated with
there a relationship between change in oestradiol and change constant concentrations of oestradiol and the percentage of
in BMD z-score (data not shown). women affected varied over the reference periods from 5%
The calibration of the three Lunar DPX DEXA instruments (reference period 2) to 17% (reference period 6). These
oestradiol concentrations could be in the early as well as inremained consistent. In the opinion of the Bona Fide company,
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R.Beerthuizen et al.
Cummings, S.R., Black, D.M., Nevitt, M.C. et al. (1993) Bone density atthe late follicular phase range, but were not fluctuating. Taking
various sites for prediction of hip fractures. Lancet, 341, 72–75.
into account all women who had amenorrhoea in our study, Cundy, T., Evans, E., Roberts, H. et al. (1991) Bone density in women
there was no relationship with the direction of change of BMD. receiving depot medroxyprogesterone acetate for contraception. BMJ, 303,
13–16.During use of the levonorgestrel implant Norplant®, reports
Cundy, T., Cornish, J., Roberts, H. et al. (1998) Spinal bone density in womenshow that there is no adverse effect on BMD (Naessen et al.,
using depot medroxyprogesterone contraception. Obstet. Gynecol., 92,
1995; Cromer et al., 1996). In another study where Norplant® 569–573.
Gbolade, B., Ellis, S., Murby, B. et al. (1998) Bone density in long term usersimplants were compared with long-term use of DMPA, no
of depot medroxyprogesterone acetate. Br. J. Obstet. Gynaecol., 105,difference in effects was found regarding distal and ultradistal
790–794.
radius measurements (Taneepanichskul et al., 1997). More Laitinen, K., Välimäki, M. and Keto, P. (1991) Bone mineral density measured
recent studies in long-term (i.e. at least 1 year) users of DMPA by dual-energy X-ray absorptiometry in healthy Finnish women. Calcif.
Tissue. Int., 48, 224–231.showed somewhat conflicting results. One study (Gbolade
Mäkäräinen, L., van Beek, A., Tuomivaara, L. et al. (1998) Ovarian functionet al., 1998) concluded that in spite of long lasting amenorrhoea
during the use of a single contraceptive implant: Implanon® compared with
no adverse effect on BMD was shown. In contrast, another Norplant®. Fertil. Steril., 69, 714–721.
Marshall, D., Johnell, O. and Wedel, H. (1996) Meta-analysis of how wellreport (Cundy et al., 1998) reiterated that DMPA is associated
measures of bone mineral density predict occurrence of osteoporoticwith a significant reduction in BMD even after correction for
fractures. Br. Med. J., 312, 1254–1259.
confounding factors such as smoking. Also, in a population- Metropolitan Height and Weight Tables (1983) Statist. Bull., Jan–Jun, 3–10.
based cross-sectional study in the USA (Scholes et al., 1999), Naessen, T., Olsson, S-E. and Gudmundson, J. (1995) Differential effects on
bone density of progestogen-only methods for contraception init was concluded that particularly in young women aged 18–
premenopausal women. Contraception, 52, 35–39.21 years BMD might adversely be affected by administration
Scholes, D., Lacroix, A.Z., Ott, S.M. et al. (1999) Bone mineral density in
of DMPA. women using depot medroxyprogesterone acetate for contraception. Obstet.
Gynecol., 93, 233–238.Trabecular bone is most sensitive to oestrogen deficiency.
Taneepanichskul, S., Intaraprasert, S., Theppisai, U. and Chaturachinda, K.Our study comprises extensive measuring of anatomical sites
(1997) Bone mineral density during long-term treatment with Norplant®with high trabecular bone content such as lumbar spine, implants and depot medroxyprogesterone acetate. A cross-sectional study
trochanter, Ward’s triangle and femoral neck, with the latter of Thai women. Contraception, 56, 153–155.
World Health Organization (1994) Assessment of Fracture Risk and itssite of more mixed composition. The site of the body measured
Application to Screening for Post-Menopausal Osteoporosis: Report of awith the highest content of cortical bone in our study was
WHO Study Group. WHO, Geneva (WHO technical report series 843).
distal radius. During use of Implanon® there was a slight (but
Received on June 23, 1999; accepted on October 4, 1999not consistent) decrease in BMD of the femoral neck. At no
time was a mean decrease observed which even approached
the clinically significant magnitude of 1 SD (WHO, 1994).
Decreases in BMD in the femoral neck and Ward’s triangle,
as observed in the Implanon® group and IUD group of the
present study, may be expected in view of the age of the study
population. This was already indicated by the Lunar Company’s
database and confirmed in a study in healthy Finnish women
(Laitinen et al., 1991). Results of the measurements at L2–L4
and of the femoral neck showed that there was no accelerated
bone loss in those women who presented with lowered BMD
at baseline. The lumbar spine and the femoral neck are of
most predictive value for future fracture risk (Cummings et al.,
1993; Marshall et al., 1996). The distal radius showed a
consistent small mean increase in BMD when compared to
the baseline situation. This increase was of similar magnitude
as with Norplant® (Naessen et al., 1995). The predominantly
‘trabecular sites’ showed small increases from baseline. During
use of Implanon® there is a small mean increase in body
weight over time, although the positive results on BMD are
not attributable to this increase in body weight. Results of the
present study indicate that Implanon® can safely be used in
young women who have not yet achieved their peak bone mass.
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Croxatto, H.B., Urbancsek, J., Massai, R. et al. (1999) A multicentre efficacy
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