The effects of Prostaglandin E2 (PGE2) and Risedronate (Ris) both separately and in combination (PGE2 + Ris) were studied on the intact aged female rat skeleton to determine whether the combination of PGE2 with an antiresorptive agent is more effective anabolically than PGE2 alone. Nine-month-old Sprague-Dawley rats were injected subcutaneously either with vehicle, 6 mg PGE2/kg per day, 1 or 5 micrograms Ris/kg twice a week, or 6 mg PGE2/kg per day plus 1 or 5 micrograms Ris/kg twice a week (PGE2 + 1 Ris or PGE2 + 5 Ris) for 60 days. After the treatment, we determined the longitudinal bone growth rate, the qualitative appearance of the primary spongiosa (PS), and the static and dynamic bone histomorphometry of the secondary spongiosa (SS) of the proximal tibial metaphysis (PTM) by examining undecalcified longitudinal sections after double-fluorescent labeling. The relative effects of these treatments on longitudinal bone growth were ranked as follows: PGE2 + 5 Ris > PGE2 + 1 Ris = basal > PGE2 > 1 microgram Ris = 5 micrograms Ris = aging. The density of the PS was ranked as follows: PGE2 + 5 Ris > PGE2 + 1 Ris = PGE2 = 5 micrograms Ris = 1 microgram Ris > basal = aging. The increase in density of the PS was the result of stimulated longitudinal growth and the action of bisphosphonate. Bone mass in the SS was ranked as follows: PGE2 + 5 Ris = PGE2 + 1 Ris = PGE2 > 5 micrograms Ris = 1 microgram Ris = aging = basal.(ABSTRACT TRUNCATED AT 250 WORDS)