1 Streekziekenhuis Koningin Beatrix, Winterswijk, The Netherlands, 2 Research and Development, NV Organon, Oss, The Netherlands, 3 Chilean Institute of Reproductive Medicine, Santiago, Chile and 4 Department of Obstetrics and Gynaecology, University of Oulu, Oulu, Finland
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Abstract |
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Key words: bone mineral density/contraceptive implant/etonogestrel/3-ketodesogestrel/17ß-oestradiol
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Introduction |
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Ovarian oestrogen production is suppressed to early follicular phase concentrations, especially during the first 6 months of use. Upon continued use, oestrogen concentrations show an increase but, due to the ovulation inhibition also present in the third year, oestrogen lacks the cyclical peaks (Mäkäräinen et al., 1998). Oestrogen deficiency leads to bone loss in pre-menopausal women or into achieving a lower peak bone mass than their age-related peers, who have a normal oestrogen status. Hypothalamic amenorrhoea in young women is associated with low serum 17ß-oestradiol concentrations and low bone mass. In situations where amenorrhoea is induced by medical treatment such as administration of depot medroxyprogesterone acetate (DMPA), a lowered oestrogen status is also observed. During use of Implanon®, amenorrhoea occurs in ~20% of women (Croxatto et al., 1999
). It is therefore important to examine the bone mineral density (BMD) of the women using this implant, together with the oestrogen concentrations, for possible associations. A randomized design would have been most desirable from a scientific point of view. However, the contraceptive choice of the women being offered such diverse methods as an implant or an intrauterine device (IUD) has to be respected and does not allow randomization.
The study presented here is a prospective, comparative study of a progestagen-only hormonal contraceptive implant and a non-hormone medicated IUD, for the duration of 2 years.
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Materials and methods |
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The initial laboratory assessments included measurement of calcitonin, parathyroid hormone (PTH), cholesterol, triglycerides and prolactin. Results had to be within the laboratory reference range, to allow inclusion into the study. During 4 successive weeks, oestradiol was measured twice a week, to get an impression of the women's pre-trial oestrogen status. This schedule was repeated at months 12 and 24, or at the moment when the women decided to stop participation in the study. At month 6, only one measurement in total was done, for logistic reasons. The three study centres comprised one urban (Santiago, Chile), one rural (Winterswijk, The Netherlands), and one suburban area (Oulu, Finland). The women were of Latin American and European ethnicity.
The Lunar DPX software Lunar Corporation, Madison, WI, USA, allowed comparison to different reference populations. For analysis of our data we used the Lunar company's female-USA/Europe dataset. To apply to our data, average BMD values of the age brackets 2029 and 3039 years were taken.
BMD measurements (g/cm2) were transformed into standard deviation (SD) scores thus providing z scores (equivalent to T-scores), by means of the following equation:
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BMD measurements were done in the anteroposterior position at the following anatomical sites: lumbar spine (L2L4), proximal femur (femoral neck, Ward's triangle, trochanter) and the distal radius. These measurements were performed at baseline, after 6 months of 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' BMD measurement done if the previous one had been done >6 months ago.
Changes in the z-score of the BMD were compared between treatment groups, using analysis of covariance, with centre, age, weight at baseline, and treatment as covariates.
The primary parameter was the change in BMD z-score at `last measurement' i.e. the last measurement done in each subject, either at month 24 or upon discontinuation.
Scatterplots were used to evaluate the relationship between (change in) oestradiol and (change in) BMD, and the relationship between weight changes and changes in the BMD. The change in body weight was compared between treatment groups with the CochranMantelHaenszel test, adjusted for centre.
The study had adequate power ( 5%, ß 20%) to detect a treatment difference in change in z-score of 0.30 between Implanon® users and IUD users.
The dual energy X-ray absorptiometry (DEXA) instruments (Lunar Corporation, Madison, WI, USA) at the three different centres were calibrated at the start of the study and at the end of the study. This was done in addition to the routine calibrations done by the staff of the respective centres. In order to have a proper comparison over time, the three study centres should not have shown a difference in equipment calibration during that period. Calibration was done by Bona Fide (Madison, WI, USA) staff using the European Spine Phantom, serial number ESP100. Analysis of the European Spine Phantom scans was performed by the Bona Fide company, who reported their conclusion in writing.
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Results |
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The calibration of the three Lunar DPX DEXA instruments remained consistent. In the opinion of the Bona Fide company, any significant changes seen in the BMD results were not attributable to instrument calibration changes.
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Discussion |
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During use of the levonorgestrel implant Norplant®, reports show that there is no adverse effect on BMD (Naessen et al., 1995; Cromer et al., 1996
). In another study where Norplant® implants were compared with long-term use of DMPA, no difference in effects was found regarding distal and ultradistal radius measurements (Taneepanichskul et al., 1997
). More recent studies in long-term (i.e. at least 1 year) users of DMPA showed somewhat conflicting results. One study (Gbolade et al., 1998
) concluded that in spite of long lasting amenorrhoea no adverse effect on BMD was shown. In contrast, another report (Cundy et al., 1998
) reiterated that DMPA is associated with a significant reduction in BMD even after correction for confounding factors such as smoking. Also, in a population-based cross-sectional study in the USA (Scholes et al., 1999
), it was concluded that particularly in young women aged 1821 years BMD might adversely be affected by administration of DMPA.
Trabecular bone is most sensitive to oestrogen deficiency. Our study comprises extensive measuring of anatomical sites with high trabecular bone content such as lumbar spine, trochanter, Ward's triangle and femoral neck, with the latter site of more mixed composition. The site of the body measured with the highest content of cortical bone in our study was distal radius. During use of Implanon® there was a slight (but not 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 L2L4 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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Notes |
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References |
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Submitted on June 23, 1999; accepted on October 4, 1999.