Pathophysiological mechanisms of estrogen effect on bone metabolism. Dose-response relationships in early...

Dose-response relationships of estrogen (E) on indices of calcium balance and bone activity were studied in normal early postmenopausal women. Calcium balance was estimated by changes in forearm bone mineral content, measured by photon absorptiometry. Bone activity was estimated by serum alkaline phosphatases (S-aPh), indicating bone formation, and by fasting urinary excretion of hydroxyproline (U-HyPro) and calcium (U-Ca), indicating bone resorption. A total of 92 female volunteers were randomized to 12 months' treatment with placebo or one of three different doses (high, medium, or low) of natural estrogens (17 beta-estradiol and estriol, 4/2, 2/1, and 1/0.5 mg, respectively), sequentially combined with the same dose (1 mg) of norethisterone acetate for 10 of the 28 cycle days. The trial was completed by 79 women. Bone mineral content declined by 2% (P less than 0.001) in the placebo group, remained constant in the low hormone group and increased by 0.8% (P less than 0.05) and 1.5% (P less than 0.01), respectively, in the medium and high hormone groups. S-aPh decreased gradually and equally by 20-25% in the three hormone groups and U-HyPro and U-Ca decreased by 30-40% during 1-yr hormone treatment, irrespective of dose. The decrease in these three indices occurred practically without exceptions. Compared to the values found in 48 normal premenopausal women the untreated postmenopausal women had increased values of S-aPh (P less than 0.001), U-HyPro (P less than 0.01), and U-Ca (P less than 0.001), and no pretreatment values were below the normal premenopausal range. After treatment the mean values of S-aPh and U-HyPro were slightly lower than the premenopausal mean values (P less than 0.01). These data strongly support the major importance of E deficiency for early postmenopausal bone loss, which is prevented by even a small substitution dose of E.