A Combination of Low Doses of 17β-Estradiol and Norethisterone Acetate Prevents Bone Loss and Normalizes Bone Turnover in Postmenopausal Women

Abstract

The effects of 17 beta-estradiol (E2) 1 mg combined with low doses of norethisterone acetate (NETA) on postmenopausal bone loss and turnover were investigated in a 2-year, randomized, double-masked, placebo-controlled trial. A total of 135 postmenopausal women with a lumbar spine bone mineral density (BMD) T-score between -2 and +2 were randomized to daily treatment with an oral tablet of either placebo, E2 1 mg/NETA 0.25 mg, or E2 1 mg/NETA 0.5 mg. Significant (p < 0.001) increases in BMD at the lumbar spine (L1-4) were observed with E2 1 mg/NETA 0.25 mg (5.2%) and E2 1 mg/NETA 0.5 mg (5.4%) compared with placebo (-0.9%). The total hip BMD increased significantly in the E2 1 mg/NETA 0.25 mg (3.1%) and E2 1 mg/NETA 0.5 mg groups (3.3%) compared with placebo. At the femoral trochanter, the increase in BMD in the E2 1 mg/NETA 0.5 mg group (6.3%) was significantly different from the placebo group (0.8%), while that in the E2 1 mg/NETA 0.25 mg group (3.3%) was not. No statistical differences were found between the active groups and placebo for the change in BMD at the femoral neck. Significant increases in BMD at the distal radius and total body were found for both E2 1 mg/NETA 0.25 mg (0.9% and 2.5%, respectively) and E2 1 mg/NETA 0.5 mg (2.1% and 3.0%, respectively) compared with placebo (-0.7% and 0.4%, respectively). At the end of the treatment, urinary pyridinoline type I collagen C-telopeptide had decreased by 65% and 60% in the E2 1 mg/NETA 0.25 mg and E2 1 mg/NETA 0.5 mg groups, respectively, while the mean serum concentrations of osteocalcin had decreased by 39% and 34%, bone-specific alkaline phosphatase by 32% and 29%, and C-terminal propeptide of type I collagen by 21% and 19% had decreased by 34-39%, 29-32%, and 19-21% in the E2 1 mg/NETA 0.25 mg and E2 1 mg/NETA 0.25 mg groups, respectively. In conclusion, combinations of E2 1 mg and NETA 0.25 or 0.5 mg prevent bone loss in postmenopausal women at the lumbar spine, hip, distal radius and total body, and normalize bone turnover.

Tibolone and low‐dose continuous combined hormone treatment: vaginal bleeding pattern, efficacy and tolerability

“…The results in the present study are in line with previous published data on tibolone [23][24][25] and low-dose continuous combined E 2 (1 mg) plus NETA (0.5 mg). 17,19 In this study, tibolone showed a better vaginal bleeding profile than low-dose E 2 /NETA reflected in a lower incidence of vaginal spotting and bleeding specifically in the first 3 months of treatment, a lower mean number of spotting and bleeding episodes, a lower number of total bleeding days and a longer time to onset of first bleeding in the tibolone group. This is a clinically relevant finding since low bleeding rates are associated with better patient adherence and considered to be a key factor in a woman's decision to initiate and continue treatment.…”

“…Bleeding rates during treatment with this lower dose regimen are reported to be low and a direct comparison of 1 mg E 2 plus 0.5 mg NETA with a conventional regimen of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate confirmed this more favourable bleeding profile with the former regimen. [16][17][18][19] Higher dose estrogen-progestogen combinations compare unfavourably with tibolone with respect to bleeding and breast-related adverse events (AEs), whereas lower dose regimens have not been compared with tibolone. 8,9,[20][21][22] Therefore, the aim of the present study was to compare the occurrence of vaginal bleeding, efficacy and tolerability of 2.5 mg tibolone with 1 mg E 2 and 0.5 mg NETA.…”

Randomized, Double-masked, 2-year Comparison of Tibolone with 17β-Estradiol and Norethindrone Acetate in Preventing Postmenopausal Bone Loss

“…Similarly, the incidence of breast tenderness and the proportion of women discontinuing the study for that reason were lower with tibolone [25]. A recent randomized study showed that lower dosages of E 2 / NETA (E 2 1 mg plus NETA 0.25 or 0.5 mg) may have a better side-effect profile than the dosage used in our study; however the ability of such lower dosages to prevent bone loss in the femoral neck in early postmenopausal women has yet to be confirmed [50].…”

New developments in HRT: low-dose therapy

“…Similarly, lower doses of oestrogen and progestogen have been shown to prevent bone loss following the menopause and, in contrast to opinion in the 1980s about the minimum effective dose, it is evident that 0.5 mg of estradiol 7 and 0.3 mg CEE 8 and even ultra-low-dose transdermal estradiol at 14 micrograms/day 9 have been shown to have a significant bone-sparing effect. This is further enhanced by the addition of progestogen such as MPA or norethisterone.…”