The aim of this study was to investigate the short and long term effects of continuous percutaneous administration of estradiol (E2) cream on skeletal turnover in women in surgical postmenopause. Forty women were randomly divided into two groups, one treated with a single daily application of 3 mg/day E2 cream continuously for 12 months, the other receiving placebo cream. Forearm densitometry was performed before and at the end of treatment. Serum E2, osteocalcin (BGP), alkaline posphatase (AP) and urinary N-telopeptide of type I collagen (NTX) were also measured at baseline, month 4 and 12 of the protocol. At month 4, bone turnover was also assessed by evaluating 99mtechnetium-methylene diphosphonate (99mTc-MDP) skeletal uptake. Changes in E2, BGP, AP and NTX as well as 99mTc-MDP skeletal uptake in hormone group vs. placebo were significant after 4 months of treatment. At month 12, proximal site densitometry showed no variation in either group whereas the percentage of variation in distal site measurements resulted significantly different with an increase in the hormone group and a reduction in the placebo group. In conclusion continuous percutaneous administration of E2 cream was effective in rapidly reducing bone turnover in postmenopausal women and in counteracting the accelerated postmenopausal bone loss.