OSTEOPOROSIS PREVENTION CLINICAL-STUDY PROGRAM

Objectives: Oestrogens are widely believed to be effective against pos tmenopausal osteoporosis. However there are some outstanding questions which still need an answer. For example, the minimal effective dose r egimen of oestradiol needs to be established and the relationship betw een oestradiol levels and efficacy on bone turnover and bone mass need s to be further clarified. Methods: Menorest(R) is being tested in the prevention of postmenopausal bone loss. A phase II/III clinical progr am, that includes two double blind, dose-ranging, placebo-controlled, parallel group, 2-year studies, has started in 58 centers in Europe an d 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(R) at different doses and regimens, in the preve ntion of bone loss in early postmenopausal women. In study 201, the tr eatment regimen is 'cyclic sequential' (24 days of transdermal oestrad iol 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 a dministration). The doses studied are 50, 75, 100 mu g/day in study 20 1, and 25, 50, 75 mu g/day in study 305, (the two studies are otherwis e identical). All 'active-dose' treated groups receive dydrogesterone 20 mg/day during the last 14 days of Menorest(R) administration and pl acebo tablets are given to the placebo patch group. The main entry cri teria are natural or surgical menopause, (with hormonal confirmation) from 1 to 6 years, with no contra-indication to HRT and with a bone mi neral 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, measu red with dual energy X-ray absorptiometry (DXA) at 2 years, in the lum bar spine BMD (L1-L4). Whole body and hip BMD are also evaluated. Mark ers of bone turnover (bone-specific alkaline phosphatase, osteocalcin and CrossLaps) are monitored throughout the study. Blood samples are d rawn on the third day of patch application at certain visits in order to monitor oestradiol levels and establish any potential correlation w ith activity on bone (BMD, bone markers). Besides routine safety analy sis, 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 a vailable, and to 370 patients for whom baseline DXA data have already been validated. The mean (+/- S.D.) age of the women included in the t wo 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 postmenopau sal 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-LA) BMD is 0.914 (+/- 0.122) g/cm(2) which correspo nds to a Z-score of -0.26 and a T-score of -1.17. Femoral neck, trocha nter and Wards triangle have a BMD which is below the mean of age-matc hed 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 c alculated and showed a value of 0.868 (+/- 0.872), which can be consid ered a good performance. Conclusions: In summary, the use of one of th e most recent techniques to assess the bone mineral content/density to gether with an accurate quality control program on all the densitomete rs used in the studies will help to improve the in-vivo BMD precision and therefore make it possible to answer the above mentioned questions .