In this study we examine the influence of number of years since menopause on spontaneous bone loss and response to hormone replacement therapy (HRT) in 274 women (56.1 +/- 4.2 years) completing two placebo-controlled HRT studies of 2 or 3 year duration. Both cross sectionally and longitudinally, bone loss in untreated women was greatest closest to menopause and declined thereafter (r = 0.34, p < 0.01 for lumbar spine bone loss and r = 0.25, p < 0.05 for femoral neck bone loss when correlated with number of years since menopause), such that the loss was eliminated in the femoral neck and bone mass increased in the spine in women >10 years after menopause. In contrast, bone turnover was consistently elevated throughout postmenopause, both cross-sectionally and longitudinally. The association with number of years since menopause was counteracted by both 1 and 2 mg estradiol combined with gestodene, piperazine, estrone sulfate in combination with norethisterone, and a combination of 2 mg estradiol and 1 mg norethisterone acetate. In addition, the response to various HRT regimens was independent of baseline bone mass. Whereas bone loss was significantly related to number of years since menopause, all HRT regimens applied arrested bone loss in healthy postmenopausal women, regardless of number of years since menopause.