Objective: A 2-year multicenter, double-blind, randomized, placebo-controlled study examined the efficacy and safety of different doses of 17beta-estradiol (E(2)) alone and continuous-combined oral formulations of E(2) and norethindrone acetate (NETA) versus placebo in the prevention of bone loss in newly menopausal women.
Design: Patients were randomized to one of seven groups: placebo, E(2) 0.25 mg, E2 0.5 mg, E(2) 1 mg, E(2) 1 mg/NETA 0.25 mg, E(2) 1 mg/NETA 0.5 mg, or E(2) 2 mg/NETA 1 mg. Treatment was a once-daily tablet taken for 26 months. The primary efficacy endpoint was the change in bone mineral density (BMD) at the lumbar spine, measured by dual-energy x-ray absorptiometry, at screening and at 13, 19, and 26 months. BMD changes at the femoral neck and trochanter were also assessed. Biochemical markers of bone metabolism were measured at baseline, and at 3, 6, 13, 19, and 26 months. Histological diagnoses of endometrial samples were tabulated for each treatment group.
Results: A total of 327 women were randomized and 189 women completed the 2-year trial. BMD at the lumbar spine decreased 2.3% in the placebo group. The lowest dose of unopposed E(2) prevented bone loss at the spine and hip. Significant increases in spine BMD compared with placebo occurred in all groups of treatment with E(2) and were more pronounced in the combination groups. Compared with placebo, women receiving active treatment experienced greater reductions in bone resorption markers. The effects were evident by 6 months and generally remained stable thereafter. Adverse events, primarily associated with the endometrium, were the most common reasons for discontinuation.
Conclusions: There is a dose-dependent effect of E(2) on BMD. The addition of NETA seems to enhance the response in BMD observed with E(2). Low doses of E(2) (1 mg and lower) can be considered for the prevention of osteoporosis, while titrating the hormone dose to individual patient's needs.