OBJECTIVE Can osteoporosis and cardiovascular risk be effectively and simultaneously prevented with transdermal estradiol replacement therapy (in combination with norethisterone acetate 1 mg per day, oral, cyclically for 12 days monthly)? METHODS A selected, representative group of healthy women with an average age of 52 years, with confirmed natural menopause for 1 to 4 years, randomly allocated to a treatment-group with hormone replacement (n = 42) and a control-group (n = 70), with homogeneous main parameters in the two groups, can be compared, without distortion of the findings, during the period of the two-year intervention study: the purely trabecular bone mass in the distal radius was specifically measured, prospectively, with the highly accurate, three-dimensional, peripheral quantitative computed tomography (thin-und multi-layer technology; Densiscan 1000) and the serum lipid, lipoprotein and apolipoprotein levels were measured (at the end of the gestagen cycle) in the morning fasting state. RESULTS One-third of the persons of the control-group showed an annual loss of trabecular bone mass of more than 3.5%. These fast-losers, who on the basis of the annual bone-destruction rates are to be classified in the upper tertiles of the two groups, suffered a loss of trabecular bone of 4.2 +/- 0.4% (mean +/- SEM) in the treatment-group, compared with 7.3 +/- 1.0% in the control-group in the first year; in the second year no loss of trabecular bone was observed in the treatment-group, while in the control-group the high rate of trabecular-bone destruction continued unchanged. The slow-losers (belonging to the middle and lower tertiles according to the bone loss rates) showed equally little change in their trabecular bone mass after the menopause, which can be described as physiological, with mean yearly values between -1.1 and +0.4%, both in the treatment-group and in the control-group. Under the transdermal hormone replacement therapy only the triglyceride and total cholesterol levels fell in comparison with the control-group, but without any significant changes in the atherogenic index, either in regard to the LDL/HDL or apolipoproteins B/A-I ratios. CONCLUSIONS To be able to make valid statements it is necessary to study the effectiveness of a measure or of a preparation for the prevention of osteoporosis in fast-losers, who are to be randomized to the respective study-groups and whose status has been confirmed by tests. Transdermal hormone replacement therapy--low estradiol dose in combination with NETA--stops the pathologically increased loss of trabecular bone only in the second year of the treatment; the antiatherogenic effect, however, is not confirmed. Only an individually adjusted therapy based on test results, with follow-up controls, can constitute an efficient, ethically justifiable postmenopausal prophylaxis of both osteoporosis and coronary heart disease.