Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study

Coleman, Robert E.; Banks, L. M.; Girgis, S. I.; Kilburn, Lucy; Vrdoljak, Eduard; Fox, John; Cawthorn, Simon; Patel, Ashraf; Snowdon, Claire; Hall, Emma; Bliss, Judith; Coombes, R. Charles

doi:10.1016/s1470-2045(07)70003-7

Cited by 401 publications

(242 citation statements)

References 17 publications

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“…Major increases in bone turnover are seen when tamoxifen is withdrawn and anastrozole or letrozole is started. These findings are similar to those seen in the IES bone substudy: in those patients who were on tamoxifen for 2-3 years and then switched to exemestane, there was a significant decrease in BMD compared with baseline within 6 months at both the lumbar spine (2.7%; P \ 0.0001) and hip (1.4%; P \ 0.0001) [24]. Thus, any benefit that tamoxifen has on bone density is lost after tamoxifen treatment ends and AIs begin.…”

Section: Discussionsupporting

confidence: 82%

A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer

McCaig

Renshaw

Williams

et al. 2009

Breast Cancer Res Treat

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International audienceALIQUOT (Anastrozole vs. Letrozole, an Investigation of Quality Of Life and Tolerability) was a prospective, open-label, randomized pharmacodynamic study designed to assess the effects of aromatase inhibitors (AIs) on bone turnover in healthy postmenopausal women with estrogen receptor-positive breast cancer. Ninety-four patients were randomized to receive either 12 weeks of letrozole (2.5 mg; = 42) followed by 12 weeks of anastrozole (1 mg), or 12 weeks of anastrozole (1 mg; = 42) followed by 12 weeks of letrozole (2.5 mg). After completion of the study period, patients in the immediate adjuvant group were either switched to tamoxifen ( = 38) or continued on anastrozole or letrozole. In the beginning of the study, 42 patients had taken tamoxifen within 3 months. Patients taking drugs likely to affect bone metabolism, including bisphosphonates, were excluded. Eighty-four patients had complete sample measurements and were included in the analysis. Prior tamoxifen therapy resulted in a significantly lower mean baseline procollagen type 1 N-terminal propeptide (PINP) compared with patients with no prior tamoxifen. There were no significant differences in bone markers between AIs at any time. By 6 months, significant increases were seen in PINP, C-terminal telopeptides (CTX), bone specific alkaline phosphatise (ALP), and urinary N-terminal telopeptides (NTX). Patients with prior tamoxifen had significantly greater increases than patients with no prior tamoxifen. Patients treated with 3 months of tamoxifen following 6 months of an AI showed a significant decrease in markers of bone resorption, serum CTX and urinary NTX. In conclusion, AI-induced bone turnover increases over time. Anastrozole and letrozole produce similar effects on bone metabolism and turnover. Stopping tamoxifen therapy and starting AIs results in a significantly greater increase in bone turnover compared with commencing AIs in tamoxifen-naïve patients. Patients given tamoxifen following AI therapy showed a decrease in markers of bone resorption

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Section: Discussionsupporting

confidence: 82%

A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer

McCaig

Renshaw

Williams

et al. 2009

Breast Cancer Res Treat

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“…The 24 month results of this substudy, and the incidence of fractures within the main trial were published previously [9]. After switching to exemestane, a statistically significant reduction in BMD and increase in bone turnover markers (BTM) were observed.…”

Section: Introductionmentioning

confidence: 86%

“…As described previously [9], study subjects were censored at the start of any extended adjuvant therapy or bisphosphonate therapy, and at the date of relapse (using data from previous visit ≥3m before any bone metastasis to minimize confounding effects on BMD and BTM). In addition, patients who stopped study treatment prior to 24m were also censored at the time of discontinuation.…”

Section: Methodsmentioning

confidence: 99%

“…Time to fracture event analysis, taking into account multiple fractures per patient was conducted. Hazard ratios are presented adjusting for age and weight, time since menopause and country fracture risk as before [9]. In addition, incidence rates were analyzed by treatment group per 1000 women years.…”

Section: Methodsmentioning

confidence: 99%

“…The randomized groups were well balanced in terms of demographics and treatments received and have been detailed previously [9]. At baseline, there were no significant differences in BMD, T-score, the proportion of osteopenic patients or levels of bone markers (Table 1).…”

Section: Demographicsmentioning

confidence: 99%

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Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study

Coleman

Banks

Girgis

et al. 2010

Breast Cancer Res Treat

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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

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Update: A 62-Year-Old Woman With a New Diagnosis of Breast Cancer

Farag¹

2008

JAMA

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Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study

Cited by 401 publications

References 17 publications

A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer

A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer

Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study

Update: A 62-Year-Old Woman With a New Diagnosis of Breast Cancer

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