Six women (mean age, 62 yr; range, 48--77 yr) who were considered to have postmenopausal osteoporosis, as demonstrated by radiological evidence of vertebral crush fractures, low intestinal calcium (Ca) absorption, and bone biopsies consistent with this diagnosis, received a pharmacological dose of 25-hydroxyvitamin D3 (25OHD3; 20 microgram/day) for 3 months. This treatment increased the serum concentration of 25OHD from 8.7 +/- 4.6 to 30.2 +/- 9.5 (SD) ng/ml (P less than 0.0025), increased the serum concentration of 24,25-dihydroxyvitamin D from 1.2 +/- 1.2 to 7.7 +/- 2.7 ng/ml (P less than 0.025) in three patients, and increased the serum concentration of 1,25-dihydroxyvitamin D from 2.1 +/- 1.7 to 4.3 +/- 1.5 ng/dl (P less than 0.025). Moreover, there were commensurate increases in fractional intestinal Ca absorption from 0.38 +/- 0.03 to 0.49 +/- 0.06 (P less than 0.025) and in urinary Ca from 69 +/- 31 to 127 +/- 67 mg/day (P less than 0.025). There were no significant changes in serum Ca (9.6 +/- 0.5 vs. 9.5 +/- 0.4 mg/dl), serum phosphorus (3.4 +/- 0.2 vs. 3.6 +/- 0.4 mg/dl) or alkaline phosphatase (87 +/- 27 vs. 91 +/- 30 IU/liter) before or after therapy. It is concluded that orally administered 25OHD3 is not only effective in raising the low intestinal Ca absorption observed in postmenopausal osteoporosis but also in increasing the serum concentrations of 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D.