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Bone density recovery after depot medroxyprogesterone acetate injectable contraception use
Contraception 77 (2008) 67 – 76
Review article
Bone density recovery after depot medroxyprogesterone acetate injectable contraception use☆ Andrew M. Kaunitz a,⁎, Raquel Arias b , Michael McClung c b
a Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL 32209, USA Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA c Oregon Osteoporosis Center, Portland, OR 97213, USA Received 28 August 2007; revised 15 October 2007; accepted 16 October 2007
Abstract Background: While depot medroxyprogesterone acetate (DMPA) is a highly effective contraceptive used by millions of women, its use is associated with bone mineral density (BMD) loss, raising concerns about long-term risk of osteoporosis and/or fractures. Study Design: We conducted a systematic review of studies published in PubMed® from 1996 to 2006, evaluating changes in BMD after discontinuation of DMPA. Ten primary clinical or observational studies were identified addressing this issue. Results: BMD consistently returned toward or to baseline values following DMPA discontinuation in women of all ages. This recovery in BMD was seen as early as 24 weeks after stopping therapy and persisted for as long as women were followed up; BMD in past DMPA users was similar to that in nonusers. Conclusions: Bone loss occurring with DMPA use is reversible and is not likely to be an important risk factor for low bone density and fractures in older women, although data on fracture risk in DMPA users are lacking. © 2008 Elsevier Inc. All rights reserved. Keywords: Depot medroxyprogesterone acetate; Contraception; Injectable; Bone mineral density
1. Introduction Depot medroxyprogesterone acetate (DMPA) is an injectable progestogen contraceptive that has been used worldwide for more than 40 years [1]. Effective and convenient, DMPA offers N2 million US women economical, long-acting, reversible hormonal contraception [1–5]. In December 2004, the US Food and Drug Administration (FDA) approved the lower-dose subcutaneous (SC) formulation (DMPA-SC 104 mg), which provides efficacy, safety and duration of action (3 months) equivalent to the older intramuscular (IM) formulation (DMPA-IM 150 mg) [6,7]. In recent years, observations of reduced bone mineral density (BMD) in current DMPA users have led to concerns
☆
This review was supported by Pfizer, including writing support provided by Genesis Healthcare. The authors were not compensated, and retained full editorial control over manuscript content. ⁎ Corresponding author. Tel.: +1 904 244 3109; fax: +1 904 244 3658. E-mail address: [email protected] (A.M. Kaunitz). 0010-7824/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2007.10.005
that DMPA-induced bone loss might lead to osteopenia and increase the long-term risk of fractures — particularly in young women who have not yet attained their peak bone mass and among perimenopausal women who may be starting to lose bone mass [1]. The effect of DMPA on BMD is related to its contraceptive action: through inhibition of gonadotropin secretion, DMPA prevents follicular maturation and ovulation and causes endometrial thinning [8,9]. However, inhibition of gonadotropin secretion also results in suppression of ovarian estradiol production, and estrogen plays an important role in the regulation of bone density in premenopausal women [10,11]. Bone resorption via osteoclast activity is down-regulated by estrogens, and in hypoestrogenemia, bone resorption exceeds bone formation [11]. The imbalance between bone resorption and bone formation results in decreases in bone mineral density. In 2004, the FDA required that a black box warning be placed on the DMPA package labeling that states, “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely
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Table 1 Summary of studies assessing BMD recovery following discontinuation of DMPA Study
Design
Postmenopausal women Orr-Walker et al. [37] Cross-sectional
Cundy et al. [28]
3-year prospective observational
Age of subjects
n (DMPA)
Mean, 60 years
34 (previous users) 312 (nonusers)
Mean, 50 years 16 (users until (range, 45–55 years) menopause)
25–51 years
Petitti et al. [40]
30–34 years
Scholes et al. [15]
Cross-sectional (international, multicenter) 4-year prospective cohort
14 discontinuing users; 22 continuing users 350
18–39 years
183 (110 who discontinued)
Clark et al. [52]
4-year prospective longitudinal
18–35 years
178 (newly initiating)
Kaunitz et al. [31]
7-year prospective matched cohort
25–35 years
248 (newly initiating)
Adolescents Scholes et al. [14]
3-year population-based 14-18 years prospective cohort
Women with endometriosis Schlaff et al. [46] 18-month randomized comparator-controlled clinical trial (North American)
Crosignani et al. [50] 18-month randomized comparator-controlled clinical trial (global)
Duration of DMPA use BMD sites
Median, 3.0 years Whole body, (range, 0.2–18.1 years) lumbar spine, proximal femur 15 (nonusers Minimum of 5 years Lumbar spine, entering natural continuous use femoral neck menopause)
Key results
No significant differences between groups at any site
Control group: 6% loss at both sites; DMPA users: little change (pb.03–b.002 between groups at Years 2 and 3)
18 nonusers
Median, 10 years (range, 3–20 years)
Lumbar spine, femoral neck
In subjects discontinuing DMPA use, lumbar spine BMD increased 3.4%/year (pb.001)
695 (never used hormonal contraception) 274 (nonusers)
≥24 months lifetime use (median, 36.4 months) Median, 11.3 months (range, 1–133 months)
Distal radius, midshaft of ulna
No significant differences between past users and never users
145 (not using hormonal contraception) 360 (users of nonhormonal contraception)
Discontinuers: b12–36 months
Lumbar spine, proximal femur, whole body Lumbar spine, total hip
Discontinuers had increases at both spine and hip (1.41%/year and 0.40%/year); at 30 months, mean BMD was similar to nonusers b12 months of DMPA use: spine BMD increased 1.0%/year after discontinuation; 24–36 months: 1.9%/year; slower recovery of hip BMD At 96 weeks following discontinuation, total hip BMD returned to near baseline (mean, −0.2% change from pretreatment); partial recovery of lumbar spine BMD (−1.2% change from pretreatment)
Up to 5 years (240 weeks) of treatment and 2 years (96 weeks) posttreatment follow-up
Lumbar spine, total hip
80 (DMPA users 90 (age, similar; Median, 12 months at baseline); 61 unexposed (range, 1–39 months) discontinued during to DMPA) follow-up
Hip, spine and whole body
Discontinuers showed greater BMD increases vs. controls at all sites (hip, 1.34%/year; spine, 2.86%/year; whole body, 3.56%/year)
18–49 years (premenopausal)
136 (DMPA-SC 104 mg)
138 (treated 6 months (with with leuprolide) 12 months of posttreatment follow-up)
Total hip, lumbar spine
18–49 years (premenopausal)
153 (DMPA-SC 104 mg)
146 (treated 6 months (with with leuprolide) 12 months posttreatment follow-up)
Total hip, lumbar spine
After 6 months of treatment, DMPA-SC group showed significant reduction only in lumbar spine BMD (median change from baseline, −1.1%); after 12 months post treatment, no significant change from baseline in either total hip or lumbar spine BMD After 6 months of treatment, DMPA-SC group showed significant reduction only in lumbar spine BMD (median change from baseline, −1.0%); after 12 months post treatment, no significant change from baseline in either total hip or lumbar spine BMD
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Premenopausal women Cundy et al. [53] Prospective observational
n (Comparison group)
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reversible. Depo-Provera contraceptive injection should be used as a long-term birth control method (e.g., longer than 2 years) only if other birth control methods are inadequate.” These statements may cause some clinicians and women to believe that DMPA should only be used as a short-term option (b2 years) [4]. Overall, current DMPA use has been clearly associated with a decline in BMD, as discussed in detail in a recent systematic review by Curtis and Martins [12]. However, the most germane issue is whether prior use of DMPA contraception increases the risk of osteoporosis or fracture in older adults many years after discontinuation of injections. Unfortunately, data assessing the impact of DMPA contraception on fracture risk are still lacking. Measurement of BMD serves as a surrogate marker of bone strength in postmenopausal women and is a readily available noninvasive method used for generally assessing osteoporotic
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fracture risk in this population (although it is unclear whether BMD serves as a useful surrogate for subsequent fracture risk among premenopausal women). The objective of this review article is to determine the degree of BMD recovery following DMPA discontinuation in younger and older reproductive-age women.
2. Materials and methods This article reviews the English-language literature related to change in BMD during and after discontinuation of DMPA therapy. The search strategy to identify appropriate publications involved querying PubMed® for all articles published from January 1996 through May 2006 using the search terms “medroxyprogesterone 17-acetate,” “medroxyprogesterone,” “bone density,” “bone resorption,” and
Fig. 1. Summary of BMD changes in postmenopausal women previously using DMPA vs. nonusers. (A) Results of a cross-sectional study (described in Table 1) of BMD (g/cm2) in postmenopausal former DMPA users (n=34) vs. nonusers (n=312); between-group differences were not significant at either site [37]. (B) Percent change from baseline in BMD over 3 years in a prospective observational study of women entering menopause [either discontinuing DMPA use at menopause without subsequent hormone replacement therapy (n=11) or non-DMPA users entering natural menopause without HRT (n=15)]. ⁎pb.03; †pb.01; ‡ pb.002; §pb.02, between-group differences [28].
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“bone demineralization, pathologic.” The search was limited as follows: females only, English only, human only and clinical trials/randomized controlled trials only. All primary published observational studies and clinical trials examining BMD recovery after discontinuation of DMPA were included. 3. Results A total of 227 publications were compiled. Of these, 41 were identified as primary clinical trials or observational studies on the topic of BMD assessments in users of DMPA [12–52]. Three additional studies were identified through review of references cited in these publications and/or review papers on the topic [53–55]. Of these 44 studies, 10 included an assessment of BMD after DMPA discontinuation [14,15,28,31,37,40,46,50,52,53]. All 10 were published in peer-reviewed journals; Table 1 summarizes the study designs and key findings of these studies (to be discussed further below). 3.1. Bone mineral density in postmenopausal former DMPA users Two studies were identified that addressed the effects of past DMPA use on BMD in postmenopausal women (Table 1; Fig. 1). Orr-Walker et al. [37] evaluated the residual effects of previous DMPA use on BMD in a crosssectional study of 346 healthy postmenopausal New Zealand women aged 60±5 years, 34 (10%) of whom had previously used DMPA. In these women, DMPA use was begun at a median age of 41 years and discontinued at a median of 2 years before menopause. As shown in Fig. 1A, BMD measurements were not significantly different between former DMPA users and nonusers; however, the authors did note that there was a trend toward lower BMD in women who had used DMPA for longer than 2 years. Orr-Walker et al. concluded that any residual effects of DMPA were small and not likely to contribute to fracture risk in the postmenopausal years. In a 3-year prospective study, Cundy et al. [28] specifically addressed the effect of DMPA used continuously up to the time of onset of menopause on the rate of early postmenopausal bone loss, compared with nonusers entering natural menopause [without the use of hormone replacement therapy (HRT)]. As shown in Fig. 1B, early menopausal bone loss was rapid in the comparison group (6% from both sites measured) over 3 years, but the DMPA users (discontinuing at onset of menopause) who did not take HRT (n=11) showed little change in BMD over this time period. In five DMPA users who were treated with HRT upon onset of menopause, BMD increased significantly at the lumbar spine and was stable at the femoral neck. These results suggested that women who use DMPA until menopause have attenuated rates of bone loss from the lumbar spine and femoral neck during the early menopausal
years, presumably because they have already lost some of the estrogen-sensitive component of bone. In summary, the evidence assessing the impact of DMPA use on BMD and/or fracture risk in postmenopausal women is sparse, but the available data do not suggest a long-term impact of previous DMPA use on postmenopausal BMD levels. More studies are needed in this age group to address actual fracture risk. 3.2. Bone mineral density after discontinuation of DMPA in premenopausal women Five studies that measured changes in BMD after discontinuation of DMPA in premenopausal women were identified (Table 1; Fig. 2): one cross-sectional [40] and four prospective studies [15,31,52,53]. The large (N=2474), international cross-sectional study (Petitti et al. [40]) included 695 women who had b6 months lifetime experience with hormonal contraception and 350 DMPA users (with at least 24 months of lifetime use). This study reported that BMD at the distal radius and midshaft ulna in former adult DMPA users was similar to that of never-users. By analyzing current users (n=133) vs. past users (n=32), Petitti et al. concluded that BMD decreased during use of DMPA, but the effect was reversible. The reversibility of bone loss associated with DMPA use in premenopausal women was further supported by the results of three prospective observational studies, summarized in Fig. 2A as annualized rates of change in lumbar spine and hip BMD following discontinuation of DMPA [15,52,53]. In each study, spine BMD increased more rapidly than hip BMD following discontinuation of DMPA; rates of increase ranged across studies from 1.41% to 3.4% per year for spine BMD and from 0.4% to 0.9% per year for hip BMD. In the Clark 2006 study [52], rates of change depended on length of DMPA use — increase in spine BMD was 1.0% per year for subjects who had used DMPA for less than 12 months, 1.7% per year for subjects who had used DMPA for 12–24 months and 1.9% per year for subjects who had used DMPA for 24–36 months prior to discontinuation. The Scholes et al. [15] 2002 study reported that, at approximately 30 months after discontinuation of DMPA, mean BMD for discontinuers was similar to that of nonusers; in the Clark et al. [52] 2006 study, mean spine BMD had also recovered to baseline levels at approximately 27–30 months after discontinuing DMPA (although hip BMD remained 2.0% lower than baseline at 30 months following discontinuation for women who had used DMPA for 12–24 months). Finally, a 7-year prospective matched-cohort study by Kaunitz et al. [31] represents the largest and longest controlled study of BMD in women using DMPA (150 mg IM formulation) conducted to date. Subjects were women aged 25–35 years using DMPA or nonhormonal contraception who were matched on the basis of race, age and current smoking status. Change in BMD as measured by dual X-ray absorptiometry was assessed for up to 4.6 years
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Fig. 2. Summary of BMD changes in premenopausal adult women discontinuing DMPA use vs. nonusers. This graph summarizes BMD recovery following discontinuation of DMPA vs. BMD changes in nonusers, including studies with measurements available for lumbar spine and femoral neck/total hip sites (see Table 1 for study descriptions). All studies reported initial declines in BMD associated with DMPA use. (A) Changes from baseline represent changes from BMD during DMPA use to BMD at end of follow-up after discontinuation (expressed as annualized rates of change). ⁎pb.001 vs. baseline (prior to DMPA discontinuation). For Clark et al. [52], results shown are for subjects who had used DMPA for 12–24 months prior to discontinuation; increase in spine BMD was 1.0% per year for those using DMPA for less than 12 months and 1.9% per year for those using DMPA for 24–36 months [15,52,53]. (B) Changes from baseline represent changes from pretreatment BMD levels (prior to DMPA initiation) at each postdiscontinuation time point. ⁎pb.05, between-group differences [31].
(240 weeks) of treatment and for up to 1.8 years (96 weeks) of posttreatment follow-up in subjects who received at least one dose of DMPA. Of the women enrolled, 42 (17%) in the DMPA-IM group and 118 (33%) in the nonhormonal group completed the 240-week treatment period. Posttreatment data were available for 91 women, including women who discontinued DMPA prior to Week 240. Consistent with other published studies, BMD in DMPA users decreased from baseline by −5.16% in total hip and −5.38% in lumbar spine; the rate of BMD decline in the DMPA-IM group was
most rapid in the first year of treatment. As shown in Fig. 2B, recovery in BMD occurred after DMPA discontinuation. Posttreatment follow-up at 96 weeks indicated an overall mean change of −0.20% in total hip BMD and −1.19% in lumbar spine BMD. Since the posttreatment period was limited by the study protocol to 2 years, the time course for full recovery was not completely delineated. Fracture rates, which were captured as adverse events, were low (3.4% and 3.8% in the DMPA users and nonusers, respectively) and similar in the two groups.
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In summary, these data all consistently demonstrate that BMD loss during DMPA use is at least partially reversible upon discontinuation in premenopausal women, with BMD returning to levels at or near baseline depending on measurement site and length of follow-up. 3.3. Bone mineral density after discontinuation of DMPA in adolescents Since accumulation of peak bone mass occurs during adolescence, there is particular concern about the use of DMPA — and its skeletal health impact — in this population. However, only one study was identified that specifically investigated BMD levels following discontinuation of DMPA in adolescents (Table 1, Fig. 3). Scholes et al. [14] conducted a population-based prospective cohort study that followed up 170 adolescent girls aged 14–18 years (including 80 who used DMPA-IM 150 mg at baseline). BMD was measured every 6 months for 24–36 months at the hip, spine and whole body, and mean BMD changes were compared between women who used DMPA, those who discontinued during the study (n=61) and women who had not used DMPA (n=90). Among women using DMPA, BMD declined significantly relative to nonusers at the hip and spine (−1.81% vs. −0.19%, pb.001 and −0.97% vs. 1.32%, pb.001, respectively) but not the whole body (0.73% vs. 0.88%, p=.78). More rapid BMD loss was observed in new users vs. women who had been using DMPA for longer than 6 months. However, discontinuation of DMPA was associated with a significantly increased BMD relative to nonusers at all anatomic sites. While use of DMPA in adolescents was associated with significant loss of BMD at the hip and spine, the significant increases in BMD soon
after discontinuation indicates that loss of bone mass was reversible. In addition, the duration of DMPA use was not shown to affect speed of BMD recovery following discontinuation. As the authors observed, “Adjusted mean BMD values for discontinuers were at least as high as those of nonusers for all anatomic sites at 12 months and at all subsequent follow-up intervals” [14]. 3.4. Bone mineral density after treatment with DMPA in women with endometriosis Two randomized, controlled clinical trials published in 2006 compared DMPA-SC (104 mg) and leuprolide (11.25 mg) therapy for treatment of endometriosis and included BMD measurements as a primary safety end point (Table 1) [46,50]. BMD was measured at baseline, after 6 months of treatment and at 6 and 12 months during a follow-up period after treatment [46,50]. In the first study by Schlaff et al. [46] (Fig. 4A), patients who received DMPA-SC had significantly less bone loss (pb.001) compared with patients receiving leuprolide at the end of active treatment. By the 12-month posttreatment follow-up, BMD scores had returned to baseline levels in the DMPAtreated but not in the leuprolide-treated women. This study also found that recovery of BMD occurs rapidly (within 12 months) after DMPA-SC discontinuation [46]. The second study, by Crosignani et al. [50], produced similar results (Fig. 4B): bone loss was observed in both treatment groups at Month 6, but the decrease was significantly less in the DMPA-SC group (pb.001 vs. leuprolide). Again, BMD returned to pretreatment levels within 12 months after discontinuation of DMPA but not after discontinuation of leuprolide [50].
Fig. 3. BMD changes in adolescents during DMPA use or following discontinuation. This graph shows mean percent change in BMD at total hip (A), spine (B) and whole body (C) for new users (n=17, 9 and 8 at 12, 18 and 24 months, respectively), prevalent users (n=26, 18 and 14) and discontinuers (n=26, 14 and 5) compared with nonuser controls (n=69, 69 and 59). Results are shown as mean±S.E., adjusted for baseline covariates (BMD, ethnicity, pregnancy, age at menarche) and time-dependent covariates (age, smoking status, calcium intake, percent body fat). Reprinted with permission from Arch Pediatr Adolesc Med 2005;159:139–144.
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Fig. 4. Posttreatment BMD recovery in women receiving DMPA-SC 104 mg or leuprolide acetate for the treatment of endometriosis. These graphs show the median percent changes in total hip and lumbar spine BMD after 6 months of treatment with DMPA-SC 104 or leuprolide and after 12 months of posttreatment follow-up (month 18 from start of study) compared with pretreatment baseline. p Values represent between-group differences. (A) North American and (B) global pivotal clinical trials of DMPA-SC 104 for the treatment of endometriosis. Reprinted with permission from Fertil Steril 2006;85:314–325 and Hum Reprod 2006;21:248–256.
These studies provide further evidence regarding the reversibility of DMPA-associated bone loss and make useful observations regarding the short-term effects of the lowerdose SC formulation on BMD. However, longer-term data for DMPA-SC or direct comparisons between the SC and IM formulations are not available.
4. Discussion 4.1. Relationship between bone mineral density and fracture risk DMPA use by women of reproductive age is associated with decreases in BMD; however, the clinical significance
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of this effect remains unknown. As reviewed in this article, studies involving DMPA treatment for up to 5 years have shown that the decline in BMD associated with DMPA use is substantially reversed after discontinuation in premenopausal women. The most critical outcome with regard to bone health is the occurrence of osteoporosis and subsequent risk of fracture [56]. Osteoporosis is a disorder characterized by low bone density, impaired bone strength and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility [57]. The key determinant of fracture risk is bone strength. In addition to low BMD, many factors are associated with risk of osteoporotic fracture, including age, cigarette smoking, low physical activity, low intake of calcium and vitamin D, race, small body size and a personal or a family history of fracture [58]. Of these, age, a history of fracture and risk of falling constitute the most important BMD-independent risk factors influencing bone mass and fracture risk [57]. Older women carry a substantially greater risk for fracture than younger women with similar BMD [59]. While the correlation between BMD and fracture risk has been studied in older women, there is little data on the effect of BMD changes on fracture risk in younger women [56,60]. In our review of existing literature, as well as a review published several years ago [61], we found no studies that evaluated the relationship between the use of progestogen-only contraception and risk of osteoporosis or fractures in older women. 4.2. Effects on bone mineral density of DMPA compared with lactation The magnitude of BMD effects associated with transient DMPA use is similar to the BMD effects observed in lactating women, and patterns of BMD recovery post DMPA use are similar to BMD recovery patterns post weaning. Several studies have reported that a transient decrease in BMD occurs during lactation with partial or full recovery after weaning [62–74]. BMD decreases during lactation by approximately 4–6% over 6 months in studies where lactating women are compared with nonlactating postpartum controls [62,63,75]. In a cross-sectional, case-control study, Karlsson et al. [64] observed a decrease in femoral neck and lumbar spine BMD in breastfeeding mothers. Several prospective, controlled and noncontrolled studies have supported the data presented by Karlsson et al. [68,76,77]. Lactation-induced BMD loss is thought to result from two physiologic changes during lactation: a significant loss of calcium in breast milk and a prolonged period of postpartum amenorrhea associated with hypoestrogenemia [78]. Evidence suggests that women fully recover bone density lost during pregnancy and lactation upon restoration of ovarian function [62,79]. The number of pregnancies and cumulative duration of lactation do not appear to be risk factors for osteoporosis [64,80]. Furthermore, hip fracture risk in older women is inversely
correlated with the number of pregnancies and is not related to duration of lactation [80,81]. 4.3. Mechanism of DMPA-associated bone loss The Cundy et al. [28] study supports the notion that DMPA-associated bone loss is due to estrogen deficiency, which mimics the physiologic mechanism of bone loss during menopause. Moreover, Cundy et al. noted that bone density was remarkably stable and early menopausal bone loss (3 years after menopause) from the lumbar spine and femoral neck was significantly attenuated in long-term users of DMPA. In addition, two studies [20,29] have demonstrated that menopausal doses of estrogen supplementation prevent decreases in BMD in adult females and adolescent DMPA users, further substantiating that decline in BMD during current DMPA use represents an estrogen-mediated process. Estrogen from an exogenous (supplemental estrogen) or endogenous (ovarian) source allows similar recovery of BMD following DMPA discontinuation, suggesting that the cellular mechanisms of estrogen action involved in bone metabolism remain intact during DMPA use. Although there is insufficient evidence to provide specific clinical guidance, some clinicians prescribe supplemental menopausal doses of oral or transdermal estrogen in long-term DMPA users who have additional risk factors for low BMD (e.g., a slender, Caucasian, perimenopausal cigarette smoker using DMPA long-term for contraception). 4.4. Position statements from professional organizations regarding DMPA use and bone health Four organizations, including the World Health Organization, the Society for Adolescent Medicine, the Society of Obstetrics and Gynecology of Canada and the American College of Obstetricians and Gynecologists, have provided position statements regarding the use of DMPA and skeletal health [56,60,82,83]. None of these organizations recommend restricting initiation or continuation of DMPA to address skeletal health concerns or routine BMD testing in DMPA users. 5. Conclusions On the basis of the evidence available for review, we conclude that transient but reversible declines in BMD occur in premenopausal women who receive DMPA. However, the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm. Accordingly, we conclude that skeletal health concerns should not restrict initiation or continuation of DMPA in adolescent girls or older reproductive-age women (aged N45 years). In the absence of other important risk factors or clinical concerns, we do not believe that routine BMD testing of women who are beginning, receiving or have received DMPA therapy is warranted. Moreover, the available evidence does not justify the
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Review article
Bone density recovery after depot medroxyprogesterone acetate injectable contraception use☆ Andrew M. Kaunitz a,⁎, Raquel Arias b , Michael McClung c b
a Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL 32209, USA Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA c Oregon Osteoporosis Center, Portland, OR 97213, USA Received 28 August 2007; revised 15 October 2007; accepted 16 October 2007
Abstract Background: While depot medroxyprogesterone acetate (DMPA) is a highly effective contraceptive used by millions of women, its use is associated with bone mineral density (BMD) loss, raising concerns about long-term risk of osteoporosis and/or fractures. Study Design: We conducted a systematic review of studies published in PubMed® from 1996 to 2006, evaluating changes in BMD after discontinuation of DMPA. Ten primary clinical or observational studies were identified addressing this issue. Results: BMD consistently returned toward or to baseline values following DMPA discontinuation in women of all ages. This recovery in BMD was seen as early as 24 weeks after stopping therapy and persisted for as long as women were followed up; BMD in past DMPA users was similar to that in nonusers. Conclusions: Bone loss occurring with DMPA use is reversible and is not likely to be an important risk factor for low bone density and fractures in older women, although data on fracture risk in DMPA users are lacking. © 2008 Elsevier Inc. All rights reserved. Keywords: Depot medroxyprogesterone acetate; Contraception; Injectable; Bone mineral density
1. Introduction Depot medroxyprogesterone acetate (DMPA) is an injectable progestogen contraceptive that has been used worldwide for more than 40 years [1]. Effective and convenient, DMPA offers N2 million US women economical, long-acting, reversible hormonal contraception [1–5]. In December 2004, the US Food and Drug Administration (FDA) approved the lower-dose subcutaneous (SC) formulation (DMPA-SC 104 mg), which provides efficacy, safety and duration of action (3 months) equivalent to the older intramuscular (IM) formulation (DMPA-IM 150 mg) [6,7]. In recent years, observations of reduced bone mineral density (BMD) in current DMPA users have led to concerns
☆
This review was supported by Pfizer, including writing support provided by Genesis Healthcare. The authors were not compensated, and retained full editorial control over manuscript content. ⁎ Corresponding author. Tel.: +1 904 244 3109; fax: +1 904 244 3658. E-mail address: [email protected] (A.M. Kaunitz). 0010-7824/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2007.10.005
that DMPA-induced bone loss might lead to osteopenia and increase the long-term risk of fractures — particularly in young women who have not yet attained their peak bone mass and among perimenopausal women who may be starting to lose bone mass [1]. The effect of DMPA on BMD is related to its contraceptive action: through inhibition of gonadotropin secretion, DMPA prevents follicular maturation and ovulation and causes endometrial thinning [8,9]. However, inhibition of gonadotropin secretion also results in suppression of ovarian estradiol production, and estrogen plays an important role in the regulation of bone density in premenopausal women [10,11]. Bone resorption via osteoclast activity is down-regulated by estrogens, and in hypoestrogenemia, bone resorption exceeds bone formation [11]. The imbalance between bone resorption and bone formation results in decreases in bone mineral density. In 2004, the FDA required that a black box warning be placed on the DMPA package labeling that states, “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely
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Table 1 Summary of studies assessing BMD recovery following discontinuation of DMPA Study
Design
Postmenopausal women Orr-Walker et al. [37] Cross-sectional
Cundy et al. [28]
3-year prospective observational
Age of subjects
n (DMPA)
Mean, 60 years
34 (previous users) 312 (nonusers)
Mean, 50 years 16 (users until (range, 45–55 years) menopause)
25–51 years
Petitti et al. [40]
30–34 years
Scholes et al. [15]
Cross-sectional (international, multicenter) 4-year prospective cohort
14 discontinuing users; 22 continuing users 350
18–39 years
183 (110 who discontinued)
Clark et al. [52]
4-year prospective longitudinal
18–35 years
178 (newly initiating)
Kaunitz et al. [31]
7-year prospective matched cohort
25–35 years
248 (newly initiating)
Adolescents Scholes et al. [14]
3-year population-based 14-18 years prospective cohort
Women with endometriosis Schlaff et al. [46] 18-month randomized comparator-controlled clinical trial (North American)
Crosignani et al. [50] 18-month randomized comparator-controlled clinical trial (global)
Duration of DMPA use BMD sites
Median, 3.0 years Whole body, (range, 0.2–18.1 years) lumbar spine, proximal femur 15 (nonusers Minimum of 5 years Lumbar spine, entering natural continuous use femoral neck menopause)
Key results
No significant differences between groups at any site
Control group: 6% loss at both sites; DMPA users: little change (pb.03–b.002 between groups at Years 2 and 3)
18 nonusers
Median, 10 years (range, 3–20 years)
Lumbar spine, femoral neck
In subjects discontinuing DMPA use, lumbar spine BMD increased 3.4%/year (pb.001)
695 (never used hormonal contraception) 274 (nonusers)
≥24 months lifetime use (median, 36.4 months) Median, 11.3 months (range, 1–133 months)
Distal radius, midshaft of ulna
No significant differences between past users and never users
145 (not using hormonal contraception) 360 (users of nonhormonal contraception)
Discontinuers: b12–36 months
Lumbar spine, proximal femur, whole body Lumbar spine, total hip
Discontinuers had increases at both spine and hip (1.41%/year and 0.40%/year); at 30 months, mean BMD was similar to nonusers b12 months of DMPA use: spine BMD increased 1.0%/year after discontinuation; 24–36 months: 1.9%/year; slower recovery of hip BMD At 96 weeks following discontinuation, total hip BMD returned to near baseline (mean, −0.2% change from pretreatment); partial recovery of lumbar spine BMD (−1.2% change from pretreatment)
Up to 5 years (240 weeks) of treatment and 2 years (96 weeks) posttreatment follow-up
Lumbar spine, total hip
80 (DMPA users 90 (age, similar; Median, 12 months at baseline); 61 unexposed (range, 1–39 months) discontinued during to DMPA) follow-up
Hip, spine and whole body
Discontinuers showed greater BMD increases vs. controls at all sites (hip, 1.34%/year; spine, 2.86%/year; whole body, 3.56%/year)
18–49 years (premenopausal)
136 (DMPA-SC 104 mg)
138 (treated 6 months (with with leuprolide) 12 months of posttreatment follow-up)
Total hip, lumbar spine
18–49 years (premenopausal)
153 (DMPA-SC 104 mg)
146 (treated 6 months (with with leuprolide) 12 months posttreatment follow-up)
Total hip, lumbar spine
After 6 months of treatment, DMPA-SC group showed significant reduction only in lumbar spine BMD (median change from baseline, −1.1%); after 12 months post treatment, no significant change from baseline in either total hip or lumbar spine BMD After 6 months of treatment, DMPA-SC group showed significant reduction only in lumbar spine BMD (median change from baseline, −1.0%); after 12 months post treatment, no significant change from baseline in either total hip or lumbar spine BMD
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Premenopausal women Cundy et al. [53] Prospective observational
n (Comparison group)
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reversible. Depo-Provera contraceptive injection should be used as a long-term birth control method (e.g., longer than 2 years) only if other birth control methods are inadequate.” These statements may cause some clinicians and women to believe that DMPA should only be used as a short-term option (b2 years) [4]. Overall, current DMPA use has been clearly associated with a decline in BMD, as discussed in detail in a recent systematic review by Curtis and Martins [12]. However, the most germane issue is whether prior use of DMPA contraception increases the risk of osteoporosis or fracture in older adults many years after discontinuation of injections. Unfortunately, data assessing the impact of DMPA contraception on fracture risk are still lacking. Measurement of BMD serves as a surrogate marker of bone strength in postmenopausal women and is a readily available noninvasive method used for generally assessing osteoporotic
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fracture risk in this population (although it is unclear whether BMD serves as a useful surrogate for subsequent fracture risk among premenopausal women). The objective of this review article is to determine the degree of BMD recovery following DMPA discontinuation in younger and older reproductive-age women.
2. Materials and methods This article reviews the English-language literature related to change in BMD during and after discontinuation of DMPA therapy. The search strategy to identify appropriate publications involved querying PubMed® for all articles published from January 1996 through May 2006 using the search terms “medroxyprogesterone 17-acetate,” “medroxyprogesterone,” “bone density,” “bone resorption,” and
Fig. 1. Summary of BMD changes in postmenopausal women previously using DMPA vs. nonusers. (A) Results of a cross-sectional study (described in Table 1) of BMD (g/cm2) in postmenopausal former DMPA users (n=34) vs. nonusers (n=312); between-group differences were not significant at either site [37]. (B) Percent change from baseline in BMD over 3 years in a prospective observational study of women entering menopause [either discontinuing DMPA use at menopause without subsequent hormone replacement therapy (n=11) or non-DMPA users entering natural menopause without HRT (n=15)]. ⁎pb.03; †pb.01; ‡ pb.002; §pb.02, between-group differences [28].
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“bone demineralization, pathologic.” The search was limited as follows: females only, English only, human only and clinical trials/randomized controlled trials only. All primary published observational studies and clinical trials examining BMD recovery after discontinuation of DMPA were included. 3. Results A total of 227 publications were compiled. Of these, 41 were identified as primary clinical trials or observational studies on the topic of BMD assessments in users of DMPA [12–52]. Three additional studies were identified through review of references cited in these publications and/or review papers on the topic [53–55]. Of these 44 studies, 10 included an assessment of BMD after DMPA discontinuation [14,15,28,31,37,40,46,50,52,53]. All 10 were published in peer-reviewed journals; Table 1 summarizes the study designs and key findings of these studies (to be discussed further below). 3.1. Bone mineral density in postmenopausal former DMPA users Two studies were identified that addressed the effects of past DMPA use on BMD in postmenopausal women (Table 1; Fig. 1). Orr-Walker et al. [37] evaluated the residual effects of previous DMPA use on BMD in a crosssectional study of 346 healthy postmenopausal New Zealand women aged 60±5 years, 34 (10%) of whom had previously used DMPA. In these women, DMPA use was begun at a median age of 41 years and discontinued at a median of 2 years before menopause. As shown in Fig. 1A, BMD measurements were not significantly different between former DMPA users and nonusers; however, the authors did note that there was a trend toward lower BMD in women who had used DMPA for longer than 2 years. Orr-Walker et al. concluded that any residual effects of DMPA were small and not likely to contribute to fracture risk in the postmenopausal years. In a 3-year prospective study, Cundy et al. [28] specifically addressed the effect of DMPA used continuously up to the time of onset of menopause on the rate of early postmenopausal bone loss, compared with nonusers entering natural menopause [without the use of hormone replacement therapy (HRT)]. As shown in Fig. 1B, early menopausal bone loss was rapid in the comparison group (6% from both sites measured) over 3 years, but the DMPA users (discontinuing at onset of menopause) who did not take HRT (n=11) showed little change in BMD over this time period. In five DMPA users who were treated with HRT upon onset of menopause, BMD increased significantly at the lumbar spine and was stable at the femoral neck. These results suggested that women who use DMPA until menopause have attenuated rates of bone loss from the lumbar spine and femoral neck during the early menopausal
years, presumably because they have already lost some of the estrogen-sensitive component of bone. In summary, the evidence assessing the impact of DMPA use on BMD and/or fracture risk in postmenopausal women is sparse, but the available data do not suggest a long-term impact of previous DMPA use on postmenopausal BMD levels. More studies are needed in this age group to address actual fracture risk. 3.2. Bone mineral density after discontinuation of DMPA in premenopausal women Five studies that measured changes in BMD after discontinuation of DMPA in premenopausal women were identified (Table 1; Fig. 2): one cross-sectional [40] and four prospective studies [15,31,52,53]. The large (N=2474), international cross-sectional study (Petitti et al. [40]) included 695 women who had b6 months lifetime experience with hormonal contraception and 350 DMPA users (with at least 24 months of lifetime use). This study reported that BMD at the distal radius and midshaft ulna in former adult DMPA users was similar to that of never-users. By analyzing current users (n=133) vs. past users (n=32), Petitti et al. concluded that BMD decreased during use of DMPA, but the effect was reversible. The reversibility of bone loss associated with DMPA use in premenopausal women was further supported by the results of three prospective observational studies, summarized in Fig. 2A as annualized rates of change in lumbar spine and hip BMD following discontinuation of DMPA [15,52,53]. In each study, spine BMD increased more rapidly than hip BMD following discontinuation of DMPA; rates of increase ranged across studies from 1.41% to 3.4% per year for spine BMD and from 0.4% to 0.9% per year for hip BMD. In the Clark 2006 study [52], rates of change depended on length of DMPA use — increase in spine BMD was 1.0% per year for subjects who had used DMPA for less than 12 months, 1.7% per year for subjects who had used DMPA for 12–24 months and 1.9% per year for subjects who had used DMPA for 24–36 months prior to discontinuation. The Scholes et al. [15] 2002 study reported that, at approximately 30 months after discontinuation of DMPA, mean BMD for discontinuers was similar to that of nonusers; in the Clark et al. [52] 2006 study, mean spine BMD had also recovered to baseline levels at approximately 27–30 months after discontinuing DMPA (although hip BMD remained 2.0% lower than baseline at 30 months following discontinuation for women who had used DMPA for 12–24 months). Finally, a 7-year prospective matched-cohort study by Kaunitz et al. [31] represents the largest and longest controlled study of BMD in women using DMPA (150 mg IM formulation) conducted to date. Subjects were women aged 25–35 years using DMPA or nonhormonal contraception who were matched on the basis of race, age and current smoking status. Change in BMD as measured by dual X-ray absorptiometry was assessed for up to 4.6 years
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Fig. 2. Summary of BMD changes in premenopausal adult women discontinuing DMPA use vs. nonusers. This graph summarizes BMD recovery following discontinuation of DMPA vs. BMD changes in nonusers, including studies with measurements available for lumbar spine and femoral neck/total hip sites (see Table 1 for study descriptions). All studies reported initial declines in BMD associated with DMPA use. (A) Changes from baseline represent changes from BMD during DMPA use to BMD at end of follow-up after discontinuation (expressed as annualized rates of change). ⁎pb.001 vs. baseline (prior to DMPA discontinuation). For Clark et al. [52], results shown are for subjects who had used DMPA for 12–24 months prior to discontinuation; increase in spine BMD was 1.0% per year for those using DMPA for less than 12 months and 1.9% per year for those using DMPA for 24–36 months [15,52,53]. (B) Changes from baseline represent changes from pretreatment BMD levels (prior to DMPA initiation) at each postdiscontinuation time point. ⁎pb.05, between-group differences [31].
(240 weeks) of treatment and for up to 1.8 years (96 weeks) of posttreatment follow-up in subjects who received at least one dose of DMPA. Of the women enrolled, 42 (17%) in the DMPA-IM group and 118 (33%) in the nonhormonal group completed the 240-week treatment period. Posttreatment data were available for 91 women, including women who discontinued DMPA prior to Week 240. Consistent with other published studies, BMD in DMPA users decreased from baseline by −5.16% in total hip and −5.38% in lumbar spine; the rate of BMD decline in the DMPA-IM group was
most rapid in the first year of treatment. As shown in Fig. 2B, recovery in BMD occurred after DMPA discontinuation. Posttreatment follow-up at 96 weeks indicated an overall mean change of −0.20% in total hip BMD and −1.19% in lumbar spine BMD. Since the posttreatment period was limited by the study protocol to 2 years, the time course for full recovery was not completely delineated. Fracture rates, which were captured as adverse events, were low (3.4% and 3.8% in the DMPA users and nonusers, respectively) and similar in the two groups.
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In summary, these data all consistently demonstrate that BMD loss during DMPA use is at least partially reversible upon discontinuation in premenopausal women, with BMD returning to levels at or near baseline depending on measurement site and length of follow-up. 3.3. Bone mineral density after discontinuation of DMPA in adolescents Since accumulation of peak bone mass occurs during adolescence, there is particular concern about the use of DMPA — and its skeletal health impact — in this population. However, only one study was identified that specifically investigated BMD levels following discontinuation of DMPA in adolescents (Table 1, Fig. 3). Scholes et al. [14] conducted a population-based prospective cohort study that followed up 170 adolescent girls aged 14–18 years (including 80 who used DMPA-IM 150 mg at baseline). BMD was measured every 6 months for 24–36 months at the hip, spine and whole body, and mean BMD changes were compared between women who used DMPA, those who discontinued during the study (n=61) and women who had not used DMPA (n=90). Among women using DMPA, BMD declined significantly relative to nonusers at the hip and spine (−1.81% vs. −0.19%, pb.001 and −0.97% vs. 1.32%, pb.001, respectively) but not the whole body (0.73% vs. 0.88%, p=.78). More rapid BMD loss was observed in new users vs. women who had been using DMPA for longer than 6 months. However, discontinuation of DMPA was associated with a significantly increased BMD relative to nonusers at all anatomic sites. While use of DMPA in adolescents was associated with significant loss of BMD at the hip and spine, the significant increases in BMD soon
after discontinuation indicates that loss of bone mass was reversible. In addition, the duration of DMPA use was not shown to affect speed of BMD recovery following discontinuation. As the authors observed, “Adjusted mean BMD values for discontinuers were at least as high as those of nonusers for all anatomic sites at 12 months and at all subsequent follow-up intervals” [14]. 3.4. Bone mineral density after treatment with DMPA in women with endometriosis Two randomized, controlled clinical trials published in 2006 compared DMPA-SC (104 mg) and leuprolide (11.25 mg) therapy for treatment of endometriosis and included BMD measurements as a primary safety end point (Table 1) [46,50]. BMD was measured at baseline, after 6 months of treatment and at 6 and 12 months during a follow-up period after treatment [46,50]. In the first study by Schlaff et al. [46] (Fig. 4A), patients who received DMPA-SC had significantly less bone loss (pb.001) compared with patients receiving leuprolide at the end of active treatment. By the 12-month posttreatment follow-up, BMD scores had returned to baseline levels in the DMPAtreated but not in the leuprolide-treated women. This study also found that recovery of BMD occurs rapidly (within 12 months) after DMPA-SC discontinuation [46]. The second study, by Crosignani et al. [50], produced similar results (Fig. 4B): bone loss was observed in both treatment groups at Month 6, but the decrease was significantly less in the DMPA-SC group (pb.001 vs. leuprolide). Again, BMD returned to pretreatment levels within 12 months after discontinuation of DMPA but not after discontinuation of leuprolide [50].
Fig. 3. BMD changes in adolescents during DMPA use or following discontinuation. This graph shows mean percent change in BMD at total hip (A), spine (B) and whole body (C) for new users (n=17, 9 and 8 at 12, 18 and 24 months, respectively), prevalent users (n=26, 18 and 14) and discontinuers (n=26, 14 and 5) compared with nonuser controls (n=69, 69 and 59). Results are shown as mean±S.E., adjusted for baseline covariates (BMD, ethnicity, pregnancy, age at menarche) and time-dependent covariates (age, smoking status, calcium intake, percent body fat). Reprinted with permission from Arch Pediatr Adolesc Med 2005;159:139–144.
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Fig. 4. Posttreatment BMD recovery in women receiving DMPA-SC 104 mg or leuprolide acetate for the treatment of endometriosis. These graphs show the median percent changes in total hip and lumbar spine BMD after 6 months of treatment with DMPA-SC 104 or leuprolide and after 12 months of posttreatment follow-up (month 18 from start of study) compared with pretreatment baseline. p Values represent between-group differences. (A) North American and (B) global pivotal clinical trials of DMPA-SC 104 for the treatment of endometriosis. Reprinted with permission from Fertil Steril 2006;85:314–325 and Hum Reprod 2006;21:248–256.
These studies provide further evidence regarding the reversibility of DMPA-associated bone loss and make useful observations regarding the short-term effects of the lowerdose SC formulation on BMD. However, longer-term data for DMPA-SC or direct comparisons between the SC and IM formulations are not available.
4. Discussion 4.1. Relationship between bone mineral density and fracture risk DMPA use by women of reproductive age is associated with decreases in BMD; however, the clinical significance
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of this effect remains unknown. As reviewed in this article, studies involving DMPA treatment for up to 5 years have shown that the decline in BMD associated with DMPA use is substantially reversed after discontinuation in premenopausal women. The most critical outcome with regard to bone health is the occurrence of osteoporosis and subsequent risk of fracture [56]. Osteoporosis is a disorder characterized by low bone density, impaired bone strength and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility [57]. The key determinant of fracture risk is bone strength. In addition to low BMD, many factors are associated with risk of osteoporotic fracture, including age, cigarette smoking, low physical activity, low intake of calcium and vitamin D, race, small body size and a personal or a family history of fracture [58]. Of these, age, a history of fracture and risk of falling constitute the most important BMD-independent risk factors influencing bone mass and fracture risk [57]. Older women carry a substantially greater risk for fracture than younger women with similar BMD [59]. While the correlation between BMD and fracture risk has been studied in older women, there is little data on the effect of BMD changes on fracture risk in younger women [56,60]. In our review of existing literature, as well as a review published several years ago [61], we found no studies that evaluated the relationship between the use of progestogen-only contraception and risk of osteoporosis or fractures in older women. 4.2. Effects on bone mineral density of DMPA compared with lactation The magnitude of BMD effects associated with transient DMPA use is similar to the BMD effects observed in lactating women, and patterns of BMD recovery post DMPA use are similar to BMD recovery patterns post weaning. Several studies have reported that a transient decrease in BMD occurs during lactation with partial or full recovery after weaning [62–74]. BMD decreases during lactation by approximately 4–6% over 6 months in studies where lactating women are compared with nonlactating postpartum controls [62,63,75]. In a cross-sectional, case-control study, Karlsson et al. [64] observed a decrease in femoral neck and lumbar spine BMD in breastfeeding mothers. Several prospective, controlled and noncontrolled studies have supported the data presented by Karlsson et al. [68,76,77]. Lactation-induced BMD loss is thought to result from two physiologic changes during lactation: a significant loss of calcium in breast milk and a prolonged period of postpartum amenorrhea associated with hypoestrogenemia [78]. Evidence suggests that women fully recover bone density lost during pregnancy and lactation upon restoration of ovarian function [62,79]. The number of pregnancies and cumulative duration of lactation do not appear to be risk factors for osteoporosis [64,80]. Furthermore, hip fracture risk in older women is inversely
correlated with the number of pregnancies and is not related to duration of lactation [80,81]. 4.3. Mechanism of DMPA-associated bone loss The Cundy et al. [28] study supports the notion that DMPA-associated bone loss is due to estrogen deficiency, which mimics the physiologic mechanism of bone loss during menopause. Moreover, Cundy et al. noted that bone density was remarkably stable and early menopausal bone loss (3 years after menopause) from the lumbar spine and femoral neck was significantly attenuated in long-term users of DMPA. In addition, two studies [20,29] have demonstrated that menopausal doses of estrogen supplementation prevent decreases in BMD in adult females and adolescent DMPA users, further substantiating that decline in BMD during current DMPA use represents an estrogen-mediated process. Estrogen from an exogenous (supplemental estrogen) or endogenous (ovarian) source allows similar recovery of BMD following DMPA discontinuation, suggesting that the cellular mechanisms of estrogen action involved in bone metabolism remain intact during DMPA use. Although there is insufficient evidence to provide specific clinical guidance, some clinicians prescribe supplemental menopausal doses of oral or transdermal estrogen in long-term DMPA users who have additional risk factors for low BMD (e.g., a slender, Caucasian, perimenopausal cigarette smoker using DMPA long-term for contraception). 4.4. Position statements from professional organizations regarding DMPA use and bone health Four organizations, including the World Health Organization, the Society for Adolescent Medicine, the Society of Obstetrics and Gynecology of Canada and the American College of Obstetricians and Gynecologists, have provided position statements regarding the use of DMPA and skeletal health [56,60,82,83]. None of these organizations recommend restricting initiation or continuation of DMPA to address skeletal health concerns or routine BMD testing in DMPA users. 5. Conclusions On the basis of the evidence available for review, we conclude that transient but reversible declines in BMD occur in premenopausal women who receive DMPA. However, the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm. Accordingly, we conclude that skeletal health concerns should not restrict initiation or continuation of DMPA in adolescent girls or older reproductive-age women (aged N45 years). In the absence of other important risk factors or clinical concerns, we do not believe that routine BMD testing of women who are beginning, receiving or have received DMPA therapy is warranted. Moreover, the available evidence does not justify the
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