The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects on bone health. We previously reported a decline in bone mineral density (BMD) following the switch from tamoxifen to exemestane in the Intergroup Exemestane Study (IES). Here we report effects of endocrine treatment withdrawal on BMD, bone turnover markers (BTM) and fracture rates.4724 patients took part in IES, and 206 patients were included in a bone substudy. BMD and BTM were assessed pre-randomization, during, and after the end of treatment (EOT). To evaluate treatment withdrawal effects, 12 and 24 month (m) post-EOT BMD results are available for 122 and 126 patients respectively. Similar patient numbers had BTM measured post EOT.Following treatment withdrawal, the differences in BMD observed between the two endocrine strategies were partially reversed. At 24m from EOT, spine BMD increased by 1.53% (95% CI 0.63 to 2.43; p=0.001) after stopping exemestane, and fell by 1.93% (95% CI -2.91 to 0.95; p=0.0002) following tamoxifen withdrawal. A similar pattern of changes was observed at the hip. At 2 years post EOT, BMD changes from baseline were similar with both treatment strategies.Corresponding inverse changes in BTM were seen, with an increase following tamoxifen withdrawal and a reduction after exemestane. A higher number of fractures occured during exemestane treatment, but fracture rates were similar after treatment withdrawal.With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required. Word count: 249Reversal of skeletal effects of endocrine treatments in the IES 3

In a cross-sectional study of 70 early postmenopausil women, regional bone measurements were compared with total body calcium (TBC*). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P < 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone,' was weak (r < 0.52, P < 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.

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