The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without calcium, to postmenopausal women with spinal osteoporosis. This single-center descriptive, double-blind, placebo-controlled, randomized, parallel group study included 32 postmenopausal white women with at least one radiographically confirmed vertebral compression fracture. Patients were randomized to one of four different dose regimen groups: (i) R-P, risedronate 20 mg/day for 14 days, followed by placebo for 42 days; (ii) R-CP-P, risedronate 20 mg/day for 14 days, followed by elemental calcium 1000 mg/day and placebo for 14 days, then by placebo for 28 days; (iii) R-CP-R-CP, risedronate 20 mg/day for 7 days, followed by elemental calcium 1000 mg/day and placebo for 21 days, then risedronate 20 mg/day for 7 days, and finally elemental calcium 1000 mg/day and placebo for 21 days; and (iv) P, placebo for 56 days. The biological response was investigated by measuring serum calcium, parathyroid hormone (PTH), and 2 h urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (DPyr/Cr) ratios at baseline and at days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 84. Overall, there were no consistent trends observed between the active group and placebo for serum calcium. In groups R-P, R-CP-P, and R-CP-R-CP, mean serum PTH levels were elevated above baseline values for the entire 56 day treatment period and remained elevated, although to a lesser extent, at the day 84 follow-up visit. The effect of calcium supplementation on PTH was variable. Urinary Pyr/Cr and DPyr/Cr ratios were decreased from baseline over the entire study period in all groups receiving risedronate. The maximum observed percent decreases from baseline for Pyr/Cr and DPyr/Cr were -46.9% and -58.8%, respectively, at day 49 in the R-CP-R-CP group. In conclusion, risedronate given orally at a dose of 20 mg/day, continuously for 7 or 14 days, resulted in the expected biological response in osteoporotic women. The time course of changes in PTH levels following cessation of dosing was unaffected by calcium supplementation. There was no evidence of a PTH-mediated rebound in bone resorption following cessation of therapy. Furthermore, based on collagen cross-link data, patients did not show an excessive reduction in bone turnover.