Bone health in estrogen-free contraception.

All progestins exert activity through binding to specific progesterone receptors. There are three different groups of progestins: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progesterone is known to bind with more affinity to androgen receptors than the C21 progestins. Animal studies by Broulik et al. [ 22 ] showed that MPA had no effect on BMD. Of various studies on progestins and bone, only studies using high doses (5 mg/day for 9 weeks) of norethindrone acetate (NETA) exerted a small positive effect on BMD. Hereby, it has been postulated by Onobrakpeya et al. [ 23 ] that this positive effect on bone is related to the 5% of NETA, which is converted to ethinyl estradiol. Additionally, norethindrone (NET) appears to have a bone-sparing effect. When compared with MPA and micronized progesterone (P4), Liu et al. [ 24 ] showed that women treated with E2 or E2 +MPA, BMD at L2–L4 increased by + 2 to + 4% over 2 years. Bone mineral density (BMD) at the spine showed a decline with MPA, P 4, and placebo treatments. With NET treatment, BMD did not change from baseline. At the femoral neck site, BMD did not change significantly for any treatment group. Bone resorption and bone formation markers decreased with E2 or E2 +MPA treatment and did not show any changes appreciably with all 3 progestin-alone treatments. DeCherney [ 25 ] reviewed studies in postmenopausal women and studies of add-back therapy in younger women and reported that norethindrone, but not MPA, has a bone-sparing effect on cortical bone but not on trabecular bone. Hartard et al. [ 26 ] compared the skeletal effects of DSG and LNG, both combined with 20 μg of EE, in young women, and found that LNG group did not lose vertebral aBMD, whereas women in the DSG group showed a decrease of − 1.5% at the distal radius and the tibia. LNG induced an increase in total cross-sectional area, indicating increased periosteal bone formation. Radial trabecular BMD declined by − 1.4 in the DSG group, while it remained unchanged in the LNG group. The lack consistency suggests that the treatment effects are small or that the study is perhaps too small to detect meaningful differences between groups.

Stowitzki et al. [ 45 ] investigated the influence of 2 mg dienogest in women with endometriosis. Hereby, serum estradiol levels after 6 months of treatment were 68 pg/ml, with no significant decrease of BMD. In accordance with these results, Klipping et al. [ 46 ] reported mean values for estradiol of 39 pg/ml after a 6-month treatment with 2 mg dienogest. Momoeda et al. [ 47 ] investigated the effect of dienogest for 12 months on BMD. This study showed a significant decrease in BMD at the lumbar spine of − 1.7% with the greatest change in the first 24 weeks with an estradiol level between 28.8 and 37.2 pg/ml. Rice et al. [ 48 ] compared serum estradiol levels of 75 μg desogestrel per day with those of 30 μg levonorgestrel daily. After 12 months of treatment, the mean estradiol levels were 74 pg/ml for desogestrel and 147 pg/ml for levonorgestrel. Data regarding bone mineral density have never been presented as the E2 levels were in a safe range and no data of adolescents in regulatory studies have been obtained. Drospirenone (DRSP) is a novel synthetic progestogen, combining potent progestogenic with anti-mineralocorticoid and anti-androgenic activities. DRSP has a high affinity for progesterone receptor (PR) and mineralocorticoid receptor (MR), and low binding to the androgen receptor (AR) like progesterone. Unlike progesterone, drospirenone has low binding to glucocorticoid receptor (GR). Neither drospirenone nor progesterone binds to the estrogen receptor (ER) (Fuhrmann et al. [ 49 ]). A study with 64 volunteers (Duijkers et al. [ 50 ]) showed that the values of estradiol at day 24 of the second cycle were below 51 pg/ml, which implies that a treatment with drospirenone had no impact in decreasing the estradiol levels below treatment initiation. The difference of estradiol levels versus women on desogestrel was statistically not significant. With this recommended dosing regimen (24 + 4), the ovary seems to secret enough endogenous estradiol for the maintenance of bone health. The drospirenone values at day 3 of the first cycle were 36.7 pg/ml for the group with a total mean value under 51 pg/ml and at day 27 of the second cycle 49.2 pg/ml. This implies that in accordance with the window of opportunity hypothesis, no reduction of estradiol levels could be described due to the application of 4 mg drospirenone over 24 days with a pause of 4 days. Consequently, no negative effect of the bone health is expected as the study endpoint values of estradiol were even higher than the baseline values (see figure 3 ). Serum estradiol levels of drospirenone were equivalent to those of dienogest and significantly not different to those of desogestrel in a study by Rice et al. [ 51 ] (54.4 pg/ml) (see figure 4 ). Therefore, 4 mg drospirenone given in a dosing regimen of 24/4 day does not seem to suppress the E2 levels under 30 pg/ml, which is considered the cutoff value for a detrimental effect on the bone (Doran et al. [ 52 ]). Further studies must evaluate if these hormonal values are enough for preventing bone mineral loss. A drospirenone-only pill has been recently approved by the FDA. There are no warnings regarding bone mineral density in the summary of product characteristics, but there is a statement that the product “leads to decreased estradiol serum levels and it is unknown if this may cause a clinically relevant loss of bone mineral density.” On the other site, the evaluated hormonal levels were all in the range of the early follicular phase [ 53 ]. Table 1 depicts the different progestogens and the estradiol levels after use of them. Table 2 depicts the main clinical data, hormonal values, and BMD data of the reported progestogens. Table 1 E2 levels after treatment with different progestogens Dienogest 37 pg/ml (Momoeda et al. [ 44 ]) Levonorgestrel 120 pg/ml (Rice et al. [ 45 ]) Etonogestrel 90 pg/ml (Beerthuizen et al. [ 46 ]) DMPA 26.6 pg/ml (Miller et al. [ 47 ]) and 25.6 pg/ml and 35.1 pg/ml (Walsh et al. [ 28 ]) Drospirenone 48.7 pg/ml (Duijkers et al. [ 50 ]) Desogestrel 54.4 pg/ml (Rice et al. [ 51 ]) Table 2 Overview of studies: main clinical data, hormonal values, and BMD data of the reported progestogens Progestogen/type of contraceptive Author/reference Study design Primary outcome Population/age Regimen/duration Estradiol (pg/ml) levels with treatment Change in BMD with treatment Etonogestrel Subcutaneous depot formulation Beerthuizen et al. 2000 [ 47 ] O, C study Change in BMD Z-score Healthy women N  = 76 Age 18–40 yrs 68 mg etonogestrel 2 years 110 Lumbar, + 0.225 g/cm 2 Femoral neck, + 0.017 g/cm 2 Ward’s triangle, + 0.083 g/cm 2 Trochanter, + 0.206 g/cm 2 Distal radius, + 0.014 g/cm 2 DMPA I.M. or S.C. injection Miller et al. 2000 [ 48 ] Study Vaginal microbial flora and epithelium Women N  = 38 Age 18–40 yrs 150 mg /3 months DMPA 6 months 26.6 n.a. Walsh et al. Cross-sectional, C study Bone health parameters Women: Cohort 1: age 18–25 yrs Cohort 2: age 35–45 yrs 150 mg/3 months DMPA DMPA use > 12 months Cohort 1 25.6 Cohort 2 35.1 Cohort 1: lumbar spine, − 5.6%; total hip, − 5.2%; distal forearm, + 2% Cohort 2: lumbar spine, − 2.4%; total hip, − 1.3%; distal forearm, + 4.6% Dienogest POP Strowitzki et al. 2010 [ 43 ] R, MC, O, P study Change in endometriosis-associated pelvic pain Women with endometriosis N  = 252 Age 18–45 yrs 2 mg/day dienogest 24 weeks 68 Lumbar spine, + 0.25% Klipping et al. 2012 [ 44 ] R, SC, DB, dose C study Ovulatory activity Healthy women N  = 104 Age 18–35 yrs 0.5, 1, 2, or 3 mg dienogest 72 days 0.5 mg, 81; 1 mg, 84; 2 mg, 39; 3 mg, 30 n.a. Momoeda et al. 2009 [ 45 ] MC, long-term treatment study Safety evaluation of adverse drug reactions Women with endometriosis N  = 138 Age ≥ 20 yrs 2 mg/day dienogest 52 weeks 28.8–37.2 Lumbar, − 1.7% Desogestrel POP Rice et al. 1999 [ 46 ] R, DB, P study Ovulatory activity Healthy women N  = 71 Age 18–40 yrs 75 μg/day desogestrel 12 months 74 174 n.a. Duijkers et al. 2015 R, C, OL, P study Hoogland score Healthy women N  = 64 Age 18–35 yrs 75 μg/day desogestrel 2 months 70 n.a. Rice et al. 1996 R, DB, P, study Ovarian suppression and vaginal bleeding Healthy women N  = 44 Age av. 28 years 30, 50, 75 μg/day desogestrel 6 months 30 μg, 54; 50 μg, 93; 75 μg, 117 n.a. Levonorgestrel POP Rice et al. 1999 [ 46 ] R, DB, P study Ovulatory activity Healthy women N  = 71 Age 18–40 yrs 30 μg/day levonorgestrel 1 year 174 n.a. Drospirenone POP Duijkers et al. 2015 R, C, OL study Hoogland score Healthy women N  = 64 Age 18–35 yrs 4 mg/day drospirenone 2 months 50.4 n.a. DMPA depot medroxyprogesterone acetate, DB double-blind, C controlled, R randomized, MC multicenter, O open-label, P parallel, SC single-center, N number of randomized/enrolled participants, n.a. not assessed, yrs years, wks weeks E2 levels after treatment with different progestogens Overview of studies: main clinical data, hormonal values, and BMD data of the reported progestogens Etonogestrel Subcutaneous depot formulation Healthy women N  = 76 Age 18–40 yrs 68 mg etonogestrel 2 years Lumbar, + 0.225 g/cm 2 Femoral neck, + 0.017 g/cm 2 Ward’s triangle, + 0.083 g/cm 2 Trochanter, + 0.206 g/cm 2 Distal radius, + 0.014 g/cm 2 DMPA I.M. or S.C. injection Women N  = 38 Age 18–40 yrs 150 mg /3 months DMPA 6 months Women: Cohort 1: age 18–25 yrs Cohort 2: age 35–45 yrs 150 mg/3 months DMPA DMPA use > 12 months Cohort 1 25.6 Cohort 2 35.1 Cohort 1: lumbar spine, − 5.6%; total hip, − 5.2%; distal forearm, + 2% Cohort 2: lumbar spine, − 2.4%; total hip, − 1.3%; distal forearm, + 4.6% Dienogest POP Women with endometriosis N  = 252 Age 18–45 yrs 2 mg/day dienogest 24 weeks Healthy women N  = 104 Age 18–35 yrs 0.5, 1, 2, or 3 mg dienogest 72 days Women with endometriosis N  = 138 Age ≥ 20 yrs 2 mg/day dienogest 52 weeks Desogestrel POP Healthy women N  = 71 Age 18–40 yrs 75 μg/day desogestrel 12 months 74 174 Healthy women N  = 64 Age 18–35 yrs 75 μg/day desogestrel 2 months Healthy women N  = 44 Age av. 28 years 30, 50, 75 μg/day desogestrel 6 months Levonorgestrel POP Healthy women N  = 71 Age 18–40 yrs 30 μg/day levonorgestrel 1 year Drospirenone POP Healthy women N  = 64 Age 18–35 yrs 4 mg/day drospirenone 2 months DMPA depot medroxyprogesterone acetate, DB double-blind, C controlled, R randomized, MC multicenter, O open-label, P parallel, SC single-center, N number of randomized/enrolled participants, n.a. not assessed, yrs years, wks weeks

The threshold values postulated by Barbieri support two distinct groups according to estradiol levels: Group A: The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml or higher does not seem to lead to an accelerate bone loss. Group B: Serum estradiol levels between 20 and 30 pg/ml as reported with the use of DMPA seem detrimental to bone health and should therefore be avoided. Group A: The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml or higher does not seem to lead to an accelerate bone loss. Group B: Serum estradiol levels between 20 and 30 pg/ml as reported with the use of DMPA seem detrimental to bone health and should therefore be avoided. All the tested progestin-only contraceptives seem to be bone safe.

For the levonorgestrel intrauterine system (IUS) today, no mechanism indicating a negative effect on bone health is apparent. However, a case-control study reported a reduced fracture risk for ever-use and long-term use of hormonal intrauterine device (IUD) (Black et al. [ 27 ]) and (Mansour D [ 28 ]). For contraceptive implants, a head-to-head study of an etonogestrel implant with one rod compared with a two-rod levonorgestrel implant showed a greater decrease in bone density. However, other implant studies could not support these findings (Safarti et al., Modesto et al., Pettiti et al. [ 29 , 30 , 31 ]). Beerthuizen et al. [ 32 ] could show that the use of the long-term progestogen implant Implanon (= 68 mg etonogestrel) for 3 years was not associated with a decrease of the BMD. The estradiol levels at the end of the study were 110 pg/ml in the Implanon group and 85 in the control group with no differences between both groups regarding bone mineral density. Some hormonal contraceptives, especially injectable depot medroxyprogesterone acetate (DMPA), have been associated with changes in markers of bone formation and turnover, bone mineral density, and fracture risk. DMPA has been shown to induce a state of hypoestrogenism that leads to a significant increase in makers of bone resorption and a decrease in BMD. One of the first studies investigating the relationship between DMPA and BMD was conducted by Cundy et al. [ 33 , 34 ], with several confirmatory studies thereafter [ 35 , 36 ]. Kyvernitakis et al. [ 37 ] identified 4189 women between 20 and 44 years of age and the use of DMPA for contraception with a first-time fracture diagnosis and matched them with 4189 random, healthy controls. They showed that DMPA exposure was associated with increased fracture risk and may have negative effects on bone metabolism, resulting in impaired bone mineral acquisition during adolescence and accelerated bone loss in adult life. The BMD decrease related to DMPA is more pronounced in women under the age of 20 and to its prolonged use [ 37 ]. Hereby, different case-control studies comprised an increased fracture risk with long-term current DMPA use (Vestergaard et al., Meier et al., Cromer et al. [ 38 , 39 , 40 ]. In 2004, the US Food and Drug Administration inserted a black box warning for DMPA labeling. Yet the response from most health organizations has been less strident. WHO and the CDC Medical Eligibility Criteria rate DMPA in women aged 18 to 45 as a category 1 method (no restriction of method uses). In women aged  45, DMPA is rated as category 2 (the advantages of the method generally outweigh the theoretical or proven risks). Walsh et al. [ 35 ] showed that DMPA had a negative effect on the BMD. When stratifying between the age and the serum E2 levels, he reported that the young users of DPMA (18–25 years) had mean serum E2 levels 12 months after treatment of 25.6 pg/ml and a significant reduction in the BMD of the lumbar spine, total hip, and distal forearm to the control group ( p  < 0.05). In contrast, no statistical difference was found in the older group (age 35–45) for these parameters when compared with controls. The mean estradiol level of these women was 35.1 pg/ml after the 12 months of treatment. DMPA has been shown to significantly decrease BMD and increase fracture risk (Cochrane Analysis; [ 37 ]). This effect may be linked to the glucocorticoid partial effect that could directly affect bone. Additionally, Miller et al. showed [ 41 ] a significant decrease in the mean serum estradiol level from 99.9 to 26.6 pg/ml ( P  < 0.001) which could also explain the detrimental effect on DMPA on bone health.

Osteoporosis is characterized by decreased bone mass and microarchitectural deterioration of the bone, leading to increased risk of fragility fracture (Kanis et al. [ 1 ]). The prevalence of osteoporosis increases with age and the burden of osteoporosis is expected to increase with aging populations. Hereby, the number of individuals at high risk of fragility fractures has been estimated to increase twofold from 158 million in 2010 to 319 million in 2040 (Kanis et al. [ 2 ]). Osteoporosis is a major public health problem, with an estimated 3.5 million fragility fractures sustained in 2010, resulting in a cost of approximately EUR 35 billion (Hernlund et al. [ 3 ]). In the absence of clear data between bone fracture and the influence of female steroidal hormones on this etiology, the following review will focus on the development of bone mineral density and female sexual hormones.

In the USA, Micronor (50 μg norethindrone) was introduced in 1971 and Ovrette (0.075 mg levonorgestrel) in 1973, long before any concerns about bone health and progestin-only oral contraceptives were raised [ 42 ]. Today, a variety of progestin-only oral contraceptives (POPs) has been introduced using 75 μg levonorgestrel; 350 μg norethindrone (norethisterone); 500 μg ethynodiol diacetate; 30 μg levonorgestrel, 75 μg desogestrel, and 500 μg lynestrenol. POPs have received little attention thus far with respect to their effect on BMD. Only one study has been identified, which included nine breastfeeding women using POPs and compared them to 19 women using barrier methods as controls. However, half of the control group ( n  = 10) was formula feeding. Although all women showed a significant decrease in lumbar spine BMD at 6 months postpartum, the decrease was significantly lower in POP users compared with that in non-users. This study conducted by Caird et al. [ 43 ] did not control for frequency of breastfeeding, and with the small number of women, it is not possible to draw any conclusion about any relationship between POPs and BMD. In 2007, Thijssen [ 44 ] concluded in a review that among adolescents (menarche to 518 years), the advantages of using progestin-only contraceptives outweigh the theoretical safety concerns regarding fracture risk. The WHO statement concludes that there should be no restriction on the use of progestin-only contraceptive methods among women who are otherwise eligible to use these methods.