Combined Oral Contraceptives and Bone Mineral Density

Summary

In a prospective study 1 56 healthy females (15-19.5 years) in Czech Republic were randomized to combined oral contraceptives (COC) with either 30 μg ethinyl estradiol (EE) plus 75 μg gestodene or 15 μg EE plus 60 μg gestodene in crossover design of 9-month intervention. Nonusers of the same age (n=28) served as controls. Bone mineral density (BMD) at lumbar spine (LS), total femur, femoral neck, distal radius, and total body, and serum markers (N-propeptide of type I procollagen, and type I collagen C-telopeptide) were measured at baseline and after 9 and 18 months.In COC nonusers, BMD significantly increased at LS and radius, while markers decreased. In COC users, BMD did not increase, with the exception of LS BMD in the 30 μg COC group (P<0.05). A difference between the 30 μg EE and 15 μg EE users was found in LS BMD changes (P<0.05), where increase in BMD was more impaired in the 15 μg EE COC users. The skeletal effects of COC remained significant after adjustments for age and smoking status. Markers declined faster in COC users during the first period, while they remained stable or even increased during the second 9 months.

In another RCT 2 in China 450 adolescents (16-18 years) were randomized to EE 30 μg plus desogestrel 150 μg or EE 35μg plus cyproterone acetate 2 mg for 2 years, and 150 women were using nonhormonal contraception as control subjects.Lumbar spine and femoral neck mean BMD values in women who used EE/desogestrel were slightly lower compared with baseline, but these effects did not reach statistical significance. The mean LS and femoral neck BMD values in women who used EE/cyproterone acetate were slightly higher compared with baseline, but there was no statistical significance (p=.789 and p=.756, respectively). The increases in mean percent change in LS and femoral neck BMD in the EE/cyproterone acetate group were less than those in the control group (1.88% vs. 0.30% and 0.98% vs. 0.49%, respectively). There were no significant differences in mean BMD of the LS and femoral neck between the users of EE/desogestrel or EE/cyproterone acetate and nonusers (p>.05).

A prospective study 3 assessed the bone metabolism in young women taking oral monophasic contraceptives (EE 20 μg + desogestrel 0.150 mg) over 5 years. Healthy women (n = 200, 19 - 22 years) were divided into two groups, one receiving COCs and the other receiving none. All the subjects underwent a BMD evaluation at spinal level L2-L4 with Dexa (Norland XR-26) and a measurement of the serum alkaline phosphatase levels and urinary excretion of OH-proline at baseline and every 12 months over 5 years. The COC group did not show any significant BMD change after 5 years, while controls demonstrated a significant increase (p < 0.01) in the bone mass content at the end of the time of observation (+7.8% after 5 years).

In another study 4 in Finland 122 adolescents (12-19 years) were divided into three groups based on estrogen-progestin contraceptive (COC; EE 35 μg or less) use: nonusers, 1-2 years of use, and use for more than 2 years. Height, weight, and the amount of exercise (ratio of work metabolic rate, h/week) as well as bone mineral content (BMC) of lumbar spine and femoral neck were measured repeatedly.There was a significant trend showing less of an increase in the mean adjusted BMC of LS in the group of adolescent women who had used COC for more than 2 years compared with the two other groups. In the mean adjusted BMC of the femoral neck, there was a significant trend of a smaller increase in COC users for more than 2 years compared with 1-2 years of use.

In an observational, prospective cohort study 5 in USA 433 postmenarcheal girls (12-18 years), who had chosen to use depot medroxyprogesterone acetate (DMPA; n = 58), oral contraceptives (COC, 20 μg EE plus 100 μg levonorgestrel ; n = 187), or were untreated (n = 188) were followed up for 24-months. Measurements of BMD at spine and femoral neck were obtained by using dual x-ray absorptiometry at baseline and 6-month intervals. Over 24 months, mean percentage change in spine BMD was as follows: DMPA, -1.5%; OC, +4.2%; and untreated, +6.3%. Mean percentage change in femoral neck BMD was as follows: DMPA, -5.2%; OC, +3.0%; and untreated, +3.8%. Statistical significance was found between the DMPA group and the other two groups.

A prospective population-based observational study 6 in Canada assessed combined hormonal contraceptives (CHC) use and adolescent women's peak areal BMD. Of 307 women with complete data, 229 (75%) used CHC. Never users (N-CHC) adolescents gained significantly more unadjusted total hip BMD +0.012 g/cm2/2-y (95% CI 0.001 to 0.023) with similar trends at all sites. N-CHC adolescents tended to have greater adjusted femoral neck BMD gain: mean difference +0.009 g/cm2 (95% CI -0.002 to 0.021). In young women N-CHC, however, adjusted femoral neck BMD decreased significantly more -0.021 g/cm2 (95%CI: -0.006; -0.036) with similar trends at other sites. BMD changes were unrelated to estrogen dose and age at starting CHC.

A study 7 compared BMD and bone turnover markers between COC and non-COC users over 12 months in college-aged females (n=62). Over 12 months, non-COC users maintained BMD at the spine, while the COC users declined 2.2% in lateral spine BMD (0.773 ± 0.014 to 0.756 ± 0.014 g/cm2, P = 0.03) and 0.7% in anterior-posterior spine BMD (1.005 ± 0.015 to 0.998 ± 0.015 g/cm2, P = 0.069). Non-COC users increased in BMD of the whole body over 12 months (P < 0.001) while COC users had no change. Women who began COCs within 4 years after menarche had lower BMD at the hip and whole body. Women taking very low dose COCs (20 mcg EE) significantly declined in lateral spine BMD in comparison to participants using low dose COCs (30/35 mcg EE).

A meta-analysis 8 assessed BMD change rate at lumbar spine (LS) and other sites in adolescent CHC users vs CHC nonusers. The 12-month LS meta-analysis with 8 paired comparisons in 1535 adolescents showed a weighted mean difference in BMD of -0.02 (95% CI -0.05 to 0.00) g/cm2 in CHC-exposed adolescents (P = 0.04). The 24-month LS meta-analysis with 5 paired comparisons in 885 adolescents showed a highly significant weighted mean BMD difference of -0.02 (95% CI -0.03 to -0.01) g/cm2 in CHC-exposed adolescents (P = 0.0006). Heterogeneity was high, I² was 96% and 85%, respectively.