Prolonged administration of natural or synthetic retinoids has been associated with significant skeletal abnormalities, including osteoporosis. We studied the effects of the synthetic retinoid fenretinide (N-4-hydroxyphenylretinamide, or 4-HPR) administered for a mean of 40 months on bone mineral density and metabolism in 66 consecutive women with early breast cancer belonging to a secondary prevention trial. The mean (+/-SD) bone mineral density at the distal and ultradistal forearm were, respectively, 0.61+/-0.08 and 0.30+/-0.05 g/cm2 in 33 treated women and 0.62+/-0.07 and 0.29+/-0.07 g/cm2 in 33 control women (p = ns for both). Also, no significant difference was observed in markers of bone formation such as bone alkaline phosphatase and osteocalcin, nor in urinary bone resorption markers such as calcium, hydroxyproline, and type I bone collagen cross-linked N-telopeptide (NTx). However, a border-line higher excretion of urinary calcium and NTx was found in the 4-HPR group after adjustment for menopausal status. We conclude that prolonged administration of 4-HPR is not associated with significant alterations of bone mineral density of the forearm. However, a trend towards an increase in bone resorption markers suggests the need for further assessment at different skeletal sites.