Osteoporosis prevention clinical study program.

Abstract

OBJECTIVES: Oestrogens are widely believed to be effective against postmenopausal osteoporosis. However there are some outstanding questions which still need an answer. For example, the minimal effective dose regimen of oestradiol needs to be established and the relationship between oestradiol levels and efficacy on bone turnover and bone mass needs to be further clarified. METHODS: Menorest is being tested in the prevention of postmenopausal bone loss. A phase II/III clinical program, that includes two double blind, dose-ranging, placebo-controlled, parallel group, 2-year studies, has started in 58 centers in Europe and South Africa. Four-hundred eighty women will be enrolled in the two studies (201 and 305). The objective of the studies is to evaluate the efficacy of Menorest at different doses and regimens, in the prevention of bone loss in early postmenopausal women. In study 201, the treatment regimen is 'cyclic sequential' (24 days of transdermal oestradiol during a 28-day cycle with progestin taken during the last 14 days of oestrogen administration). In study 305 the treatment regimen is "continuous sequential' (28 days of transdermal oestradiol during, a 28-day cycle with progestin taken during the last 14 days of oestrogen administration). The doses studied are 50, 75, 100 micrograms/day in study 201, and 25, 50, 75 micrograms/day in study 305, (the two studies are otherwise identical). All 'active-dose' treated groups receive dydrogesterone 20 mg/day during the last 14 days of Menorest administration and placebo tablets are given to the placebo patch group. The main entry criteria are natural or surgical menopause, (with hormonal confirmation) from 1 to 6 years, with no contra-indication to HRT and with a bone mineral density (BMD) at the lumbar spine with a T-score between 0 and -3. Women with severe vasomotor symptoms are excluded from the studies. The primary efficacy variable is the mean change from baseline, measured with dual energy X-ray absorptiometry (DXA) at 2 years, in the lumbar spine BMD (L1-L4). Whole body and hip BMD are also evaluated. Markers of bone turnover (bone-specific alkaline phosphatase, osteocalcin and CrossLaps) are monitored throughout the study. Blood samples are drawn on the third day of patch application at certain visits in order to monitor oestradiol levels and establish any potential correlation with activity on bone (BMD, bone markers). Besides routine safety analysis, lipid profile and coagulation factors are also monitored. Special attention is drawn to endometrial safety with endometrial aspiration or trans vaginal sonography (TVS) performed before study start, after 1 year and at 2 years of treatment. RESULTS: Data presented here refer to 146 patients for whom demographics and clinical data are already available, and to 370 patients for whom baseline DXA data have already been validated. The mean (+/-S.D.) age of the women included in the two studies is 53.4 (+/-3.2) with a menopausal age of 38.3 (+/-19.6) months. None of the women who entered the study had severe postmenopausal symptoms as shown by a mean number of hot flushes of 2.2 (+/-2.6) per day, during the last 14 days before inclusion. The mean (+/-S.D.) lumbar spine (L1-L4) BMD is 0.914 (+/-0.122) g/cm2 which corresponds to a Z-score of -0.26 and a T-score of -1.17. Femoral neck, trochanter and Wards triangle have a BMD which is below the mean of age-matched controls but still within the normal range (Z-scores between 0 and -1). Only the whole body BMD is over the mean of age-matched controls, with a Z-score of 0.32. The in-vivo precision mean (+/-S.D.), was calculated and showed a value of 0.868 (+/-0.872), which can be considered a good performance. CONCLUSIONS: In summary, the use of one of the most recent techniques to assess the bone mineral content/density together with an accurate quality control program on all the densitometers used in the studies will help to improve the in-vivo BMD precision and therefore mak