A three-year longitudinal evaluation of the forearm bone density of users of etonogestrel- and levonorgestrel-releasing contraceptive implants.

Abstract

The aim of this study was to evaluate bone mineral density (BMD) at baseline and at 18 and 36 months of use of etonogestrel (ENG)-and levonorgestrel (LNG)-releasing contraceptive implants. This is a continuation of a previous study in which BMD was evaluated at baseline and at 18 months of use.
A total of 111 women, 19-43 years of age, were randomly allocated to use one of the two implants. At 36 months of follow-up, only 36 and 39 women were still using the ENG- and LNG-releasing implants, respectively. BMD was evaluated at the distal and at the ultra-distal radius of the non-dominant forearm using dual-energy X-ray absorptiometry.
There was no difference in the BMD of users of either implant at 18 and at 36 months. BMD was significantly lower at 18 and at 36 months at the distal radius in both groups of users compared to pre-insertion values; however, no difference was found at the ultra-distal radius.
Women 19-43 years of age using either one of these two contraceptive implants for 36 months had lower BMD values at the distal radius compared to pre-insertion values; however, no difference was found at the ultra-distal radius.

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BioMed Central
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Reproductive Health
Open Access
Research
A three-year longitudinal evaluation of the forearm bone density of
users of etonogestrel- and levonorgestrel-releasing contraceptive
implants
Cecilia Monteiro-Dantas, Ximena Espejo-Arce, Jeffrey F Lui-Filho,
Arlete M Fernandes, Ilza Monteiro and Luis Bahamondes*
Address: Human Reproduction Unit, Department of Obstetrics and Gynecology, School of Medicine, Universidade Estadual de Campinas
(UNICAMP), 13084-971, Campinas, SP, Brazil
Email: Cecilia Monteiro-Dantas - mariaceciliadantas@bol.com.br; Ximena Espejo-Arce - x_espejo@yahoo.com.br; Jeffrey F Lui-
Filho - jeffrey@fcm.unicamp.br; Arlete M Fernandes - arlete@fcm.unicamp.br; Ilza Monteiro - ilza@caism.unicamp.br;
Luis Bahamondes* - bahamond@caism.unicamp.br
* Corresponding author
Abstract
Background: The aim of this study was to evaluate bone mineral density (BMD) at baseline and
at 18 and 36 months of use of etonogestrel (ENG)-and levonorgestrel (LNG)-releasing
contraceptive implants. This is a continuation of a previous study in which BMD was evaluated at
baseline and at 18 months of use.
Methods: A total of 111 women, 19–43 years of age, wererandomly allocated to use one of the
two implants. At 36 months of follow-up, only 36 and 39 women were still using the ENG- and
LNG-releasing implants, respectively. BMD was evaluated at the distal and at the ultra-distal radius
of the non-dominant forearm using dual-energy X-ray absorptiometry.
Results: There was no difference in the BMD of users of either implant at 18 and at 36 months.
BMD was significantly lower at 18 and at 36 months at the distal radius in both groups of users
compared to pre-insertion values; however, no difference was found at the ultra-distal radius.
Conclusion: Women 19–43 years of age using either one of these two contraceptive implants for
36 months had lower BMD values at the distal radius compared to pre-insertion values; however,
no difference was found at the ultra-distal radius.
Background
Although hormonal contraceptive methods are in use
worldwide, their effect on bone mineraldensity (BMD) is
a controversial issue, particularly with reference to the use
of progestogen-only (p-only) methods [1]. Users of hor-
monal contraceptives include women of different ethnic
groups and ages, ranging from adolescence through the
final reproductive years. The impact of these contraceptive
methods on BMD may be measured during use, after dis-
continuation or in the post menopause, and may also be
evaluated according to bone loss or risk of osteoporotic
fracture [1].
It has been well-established that hypo-estrogenism is one
of the most important factors related to bone formation
and resorption during a woman's life time [2,3] and it is
Published: 12 November 2007
Reproductive Health 2007, 4:11doi:10.1186/1742-4755-4-11
Received: 4 September 2007
Accepted: 12 November 2007
This article is available from: http://www.reproductive-health-journal.com/content/4/1/11
© 2007 Monteiro-Dantas et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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also known that the use of some of the p-only contracep-
tive methods, mainly the injectable depot-medroxypro-
gesterone acetate (DMPA), affects serum levels of estradiol
[4,5] For this reason and based on several publications
showing that the use of DMPA may affect BMD [4,6-8],
the US Food and Drug Administration [9] and the United
Kingdom Committee on the Safety of Medicines [10]
required inclusion in the package insertof DMPA of a
warningthat the drug may impair BMD.
Although a recommendation issued by the World Health
Organization (WHO) also established some restrictions
to the use of DMPA, principally in adolescents and in
women in the menopausal transition [11], it has also
established that the data on levonorgestrel (LNG)-releas-
ing implants suggest no adverse effect on BMD and rec-
ommended no restriction on the use of other p-
onlycontraceptive methods by women who are eligibleto
use them [11].
Since data on BMD in users of etonogestrel (ENG)- and
LNG-releasing contraceptive implants is scarce [8,12-15],
this study was conducted with the aim of evaluating BMD
prior to insertion and following 36 months of use in
women who opted to use ENG- and LNG-releasing sub-
dermal contraceptive implants.
Methods
This is a continuation of a previous study in which data
was presented on BMD levels prior to insertion and at 18
months of use of these two types of contraceptive implant
[15]. Initially, a total of 111 women were evaluated at the
Human Reproduction Unit, Department of Obstetrics and
Gynecology, School of Medicine, Universidade Estadual
de Campinas (UNICAMP), Campinas, Brazil. The Ethical
Committee of the institutionapproved the study, and all
participants signed an informed consent form prior to
admission.
The methods of this study have been published previously
[15], together with the results of BMD at baseline and at
18 months of use. Briefly, the women comprised a subset
of participantsfrom a larger study conducted by the
UNDP/UNFPA/World Bank/WHO Special Programme in
Research Training in Human Reproduction, World Health
Organization. Women requesting an implant as a contra-
ceptive method were randomly allocated to one ofthe two
kinds of implant using a computer-generated randomiza-
tion system and sealed envelopes. Fifty-six women
received a single-rod, ENG-releasing implant (Implanon®,
NV Organon, Oss, The Netherlands) and 55 women
received a two-silicone-rod, LNG-releasing implant
(Jadelle®, Bayer-Schering Pharma Oy, Turku, Finland). All
the insertions were performedwithin the first 5 days of the
menstrual cycle and there wasno wash-out time between
the last contraceptive method usedand implant insertion.
Women were excluded following these criteria: pregnan-
tor lactating within the 12 months preceding enrolment,
presented chronic diseases such as diabetesmellitus,
chronic renal failure, hyper/hypothyroidism, hyper/
hypoparathyroidism, hepatitis, cancer or pituitary dis-
eases and used calcium supplementation and/or vitamin
D, anticonvulsants, corticosteroids, thiazide diuretics or
drugs forthe treatment of thyroid disease. Nine women
(four in the Implanon® groupand five in the Jadelle®
group) were in amenorrhea at the time of insertion due to
the past use of DMPA.
Based on a previous study [14], sample size was estimated
at 48 women in each group assuming a difference in BMD
of0.014 g/cm2 between pre-insertion and 18 months of
implant use, an α of 0.20, β of 0.05, and a difference of
0.008 [16].
Definition of variables
The dependent variable, BMD, was defined as the rela-
tionship between bone mineral content (g/cm2) and the
area of the bone measured. The independent variable was
the kind of implant used by the woman. The control vari-
ables included race, number of pregnancies and deliver-
ies, time of exclusive and partial breast-feeding, body
mass index (BMI, kg/m2), duration of exercise practice,
smoking habits [17], and coffee and alcohol consumption
patterns [18].
Bone mineral density measurement
BMD was measured in three opportunities in the non-
dominant forearm at distal and ultra-distal radius with
the same equipment of dual-energy X-ray absorptiometry
(DXA) (DTX-200; Osteometer Meditech A/SCo., Rodovre,
Denmark). Two measurements of BMD were taken in
each woman: at the distal radius (where cortical bone pre-
dominates), at the point where the radius is 8 mm from
the ulna; and at the ultra-distal radius near the articulation
with the carpal bones (where trabecular bone predomi-
nates [65%]). The equipment identified the 8 mm dis-
tance between ulna and radius. This ensured that the same
area was assessed every time. The equipment was cali-
brated by twice-daily phantom measurements with a
device provided by the manufacturer. The calibration,
positioning, assessment and calculation were performed
automatically in order to minimize the operator errors.
The in vivo accuracy is >97% and precision >99% and the
coefficient of variation (CV) was 0.8%.
Statistical analysis
Comparison of demographic, anthropometric and obstet-
ric variables and BMD between the two groups was per-

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formed using Pearson and Yates' χ2 tests as appropriate.
To compare BMD at baseline and at 36 months, Wil-
coxon's non-parametric test or Student's t-test was used
[19]. The data are presented as mean ± standard deviation
(SD).
Results
Of the 111 women who underwent BMD measurement
prior to insertion and at 18 months of implant use, only
36 and 39 women were still in use of Implanon® and
Jadelle®, respectively, at 36 months of evaluation. The
decrease in the number of cases was due to premature
removals. The mean age of women at implant insertion
was 27.9 ± 0.7 and 27.1 ± 0.6 (mean ± SEM) years and
body mass index (BMI, Kg/m2) was 24.0 ± 0.5 and 24.8 ±
0.5 for Implanon and Jadelle users, respectively. At 18
months of use, BMI increased significantly to 24.7 ± 0.5 in
Implanon users (P < 0.021) and 25.6 ± 0.5in Jadelle users
(P < 0.001) [15] and at 36 months of use was 25.4 ± 0.6
and 24.4 ± 0.6, respectively for both groups of users.
There were no significant differences at pre-insertion in
number of pregnancies and deliveries in the two groups.
In both groups, almost 40% of the women were house-
wives and ~15% were professional workers; 77% of
Implanon users and 82% of Jadelle users were white. At
pre-insertion, combined oral or injectable contraceptives
were used by 45% and 35% in the Implanon and Jadelle
groups, respectively. DMPA was used by four and five
women in both groups. The remaining women were users
of non hormonal contraceptive methods before implant
insertion. Fourteen women in the Implanon group and 10
in the Jadelle group were in amenorrhea at 18 months of
evaluation. Only two women in the Implanon® group
were in amenorrhea at 36 months of evaluation.
The BMD at the distal radius was significantly lower at 18
and at 36 months of use compared with baseline measure-
ments in both Implanon® users (-5.90%) (P < 0.001) and
Jadelle® users (-4.44%) (P < 0.002). However, at the ultra-
distal radius, there were no significant differences in BMD
at 18 and 36 months compared with baseline values in
either group of implant users (Table 1). Moreover, there
were no significant differences in BMD between users of
Implanon® and Jadelle® at baseline or at 18 and 36 months
of use.
Discussion
Our results show that there were no significant differences
in BMD at ultra-distal radius, in which trabecular bone
predominates, between the users of the two types of sub-
dermal contraceptive implants prior to implant insertion
or at 18 and at 36 months of use, and these results were
almost identical to those found at pre-insertion and at 18
months of use [15] albeit there was a significant reduction
in BMD at the distal radius in both groups of women.
These results are in agreement with those reported from a
previous study [14] in which BMD was evaluated in
Implanon® users at pre-insertion and at 2 years of use at
the spine, femoral neck, Ward's triangle, trochanter, and
distal radius. They reported BMD to be similar prior to
insertion and at 24 months of use, although a slight
decreasein BMD was observed at the femoral neck; how-
ever, this decrease was less than one SD [20].
With respect to the group that used Implanon®, in theory
our results were to be expected because although this
implant inhibits ovulation, estrogen only decreased to
early follicular phase levels at the beginning of use. More-
over, estrogen levels show a tendency to increase over the
years of use and amenorrhea, due to endometrial effect
[21], has been reported in ~20% of users, a higher propor-
tion than the ~5% observed in our study group. The
present data is important, since we evaluated ENG-releas-
ing implant users at the end of the approved time of use
of this implant (3 years), albeit evidence suggests that the
duration of the use may be extended without replacement
up to 5 years [22].
Table 1: Bone mineral density according to the type of implant used, section of the forearm and duration of use.
BMD (g/cm2)
Distal radius
P-value Ultra-distal radius
P-value
Implanon (n = 36)
Baseline
18 months
36 months
Jadelle (n = 39)
Baseline
18 months
36 months
0.475 (0.032)
0.454 (0.040)
0.447 (0.038)
0.406 (0.057)
0.390 (0.034)
0.396 (0.048)
<0.0001
<0.0001
0.1041
0.2491
0.474 (0.002)
0.459 (0.040)
0.453 (0.058)
0.395 (0.015)
0.398 (0.028)
0.401 (0.072)
<0.0001
0.0022
0.7087
0.4705
All values are mean ± SD

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In the group of users of the LNG-releasing implant
(Jadelle®), the results were also as expected, since luteal
activity was found to increase over the years of use as
serum LNG declined. Moreover, serum estradiol levels
were very similar between users and non-user controls
[23,24]. Additionally, our results were in agreement with
those of previous longitudinal and cross-sectional studies
which showed no significant differences in BMD, even in
adolescents [8,12,13,25-27].
The finding that BMD was significantly lower at 18 and 36
months of use at distal radius is less important than any
changes observed at ultra-distal radius in which trabecular
bone predominates. This finding could be an indicator
that the BMD changes through the time of use. However,
the percentage of reduction on BMD at distal radius
ranged only from -3.2% to -5.9% in both groups of users
at 18 and 36 months of use when compared to baseline
values. The strengths of our study are the fact that the users
were evaluated in a longitudinal manner at pre insertion
and at 18 and 36 months of use and that Implanon® was
compared with Jadelle® The limitations of the study
include the fact that the number of women was less at 36
months than at 18 months of use and that BMD was
measured only atthe forearm, which is less predictive of
fracture risk than the lumbar spine or the femoral neck,
althoughforearm BMD also provides a good predictive
value [28].
BMD evaluated at the ultra-distal radius is less predictive
than BMD at the hip for hip fractures and less accurate at
predicting vertebral fractures than hip or spine BMD [29].
It is stated that the relative risk (95% Confidence Interval
[CI]) of fracture per SD of reduction when BMD was
measured at ultra-distal radius was 1.5 (95% CI 1.3–1.8),
1.7 (95% CI 1.5–1.9), and 1.7 (95% CI 1.4–2.0) for hip,
vertebral, and forearm, respectively [28]. BMD measured
at the femoral neck or total hip is a strong predictor of hip
fracture and predicts risk of all fractures in comparison to
peripheral BMD measure [28]. Peripheral measurements
could beused as an initial screening test and those women
with low BMD will need to be referred for BMD of the hip
or spine. In a recent systematic review on the use of steroi-
dal contraceptives and bone fractures in women [30] it
was stated that there were no trials with fracture as out-
come and that decreased BMD was observed only among
users of DMPA with inconsistent results for implants
users.
Furthermore, since the participating women were young
the possibility of BMD being affected was very low mainly
if we consider that BMD is a very soft clinical outcome and
fracture is the most important indicator of bone health.
BMD must be considered a continuous risk factor during
lifetime and the lowerthe BMD the higher the risk of frac-
ture. The estimates percentage of lifetime risk of hip frac-
ture for white women at the age of 50 at the following
three T-scores: zero, -2.0, and -3.5 were 10%, 27%, and
49%, respectively. However, these estimative were differ-
ent for BMD at forearm or spine [31].
In addition, 36 months of use may be too short a time,
since the effects of hormonal contraceptives may be
observed over many years of use and following discontin-
uation, although it has been suggested that the effect of
the past use of p-only contraceptives on BMD may be
eliminated following discontinuation of use [8,32].
Conclusion
Our data do not allow conclusions to be drawn about the
effect of these implants on adolescents or in women in the
menopausal transition. The reduction observed at the dis-
tal radius, although within the limit of 1 SD, must be ana-
lysed with caution because it is not possible to conclude
whether this loss has any clinical significance over long-
term use or if it has any effecton postmenopausal fracture
risk [33]. Additionally, it is important to take into account
that many women use hormonal contraceptive methods
for a short period of time and consequently any deleteri-
ous effect could be counterbalance by a recovery after dis-
continuation. In conclusion, BMD was significantly lower
at 18 and at 36 months of use compared to pre insertion
values in users of both contraceptive implants at the distal
radius; however, no differences were found at the ultra-
distal radius. These results could be indicating apparently
a non severe impact on BMD. This cohort of women is
currently being followed-up and BMD will be measured
again at 60 months of use if the number of users remains
adequate at that time.
Abbreviations
BMD: Bone mineral density
BMI: Body mass index
CV: Coefficient of variation
DEXA: Double X-ray absorptiometry
DMPA: Depot medroxyprogesterone acetate
ENG: Etonogestrel
LNG: Levonorgestrel
UNDP: United Nations Development Programme
UNFPA: United Nations Fund for Population Affaires
UNICAMP: Universidade Estadual de Campinas

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SD: Standard deviation
WHO: World Health Organization
Competing interests
The author(s) declare that they have no competing inter-
ests.
Authors' contributions
CM-D, XEA, JFL-Fi, AMF, IM, LB contributed equally
because all made substantive intellectual contributions to
conception and design, acquisition of data, analysis, and
interpretation and have been involved in the writing of
the manuscript and have given final approval of the ver-
sion submitted for publication.
Acknowledgements
The Fundação de Amparo a Pesquisa do Estado deSão Paulo (FAPESP), Bra-
zil provided partial financial support under award #03/083917. The contra-
ceptive implants were donated by UNDP/UNFPA/World Bank/WHO
Special Programme in Research Training in Human Reproduction, World
Health Organization, Geneva, Switzerland, as part of the study #A15229.
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