Exemestane and bone Aromatase inhibitors Adjuvant breast cancer treatment associated with bone loss
Exemestane is superior to tamoxifen in the first-line treatment of advanced breast cancer, and has also been evaluated in the adjuvant treatment setting. Although results from direct comparisons with tamoxifen are not expected for some time, data from the Intergroup Exemestane Study (IES), evaluating sequential therapy with tamoxifen for 2–3 years followed by exemestane for 2–3 years, compared with 5 years of tamoxifen therapy, have shown a significant advantage in favour of the sequential treatment option, with improvements in both disease-free and overall survival. Exemestane, in contrast to the non-steroidal agents, has weak androgenic activity. It was postulated that this might result in less adverse effects on bone.70 This provided some support for the potentially different mechanism of action of exemestane. However, in another biochemical study, exemestane was found to increase levels of bone turnover markers71 and in the Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) study, which compared the effects of all three clinically available aromatase inhibitors in postmenopausal women, no significant differences in the profile of biochemical markers of bone metabolism were seen. Of note, changes in parathyroid hormone were similar with all three agents, arguing against an anabolic effect of exemestane.
Results of a placebo-controlled trial of exemestane in early breast cancer have recently been published. In this study, 147 patients with low risk early breast cancer were randomized to receive treatment with exemestane 25 mg/day or placebo. Patients had a baseline DXA scan of the spine and hip, and follow-up assessments occurred annually. After 1 year, the BMD of patients in the exemestane group decreased by 2.17% and 2.72% at the spine and hip, respectively. However, bone loss in the placebo group was somewhat greater than expected, at 1.84% and 1.48% at the spine and hip, respectively. As a result, there was no significant difference between the two treatment groups at the lumbar spine, although the difference in hip BMD did reach statistical significance (p=0.024). None of the women were taking calcium or vitamin D supplements, and recent analysis has confirmed that many of these women were vitamin D deficient.74 In a 1-year follow up to the study after discontinuation of exemestane, the loss of BMD was partially reversed.
The effect of exemestane on markers of bone turnover was also assessed in this study. Exemestane was associated with significant increases in both markers of formation and resorption. In the exemestane group, levels of P1NP and CTX increased from baseline by 44% and 35%, respectively. However, levels of P1NP and CTX in the placebo group decreased by only 4% (p<0.001) and 5% (p=0.012), respectively.
The increase in bone resorption was consistent with the bone loss observed, while the increase in bone formation markers can be attributed to the coupling of bone formation to bone resorption.
Data from the bone sub-protocol of the IES study have recently become available.75 This study measured BMD and bone markers of resorption and formation in 206 patients at baseline, 6, 12 and 24 months. Patients who remained on tamoxifen showed no significant change from baseline in BMD. In patients who switched to exemestane, the mean rates of bone loss 6 months after tamoxifen cessation were 2.7% and 1.2% at the spine and hip, respectively. Thereafter, bone loss continued but at a slower rate of 0.5–1% per year. After 2 years, the change from baseline in BMD was 3.6% at the spine and 2.4% at the hip. Despite the more modest rate of bone loss seen in this bone sub-study, a significant increase in the incidence of fractures was observed in the IES study as a whole. With a median follow-up in all participants of 58 months and median exposure to exemestane of 30 months, 162 (7%) of patients in the exemestane group experienced a fracture compared with 115 (5%) patients in the tamoxifen group (odds ratio 1.45 [1.13–1.87]; p=0.003).
Exemestane is superior to tamoxifen in the first-line treatment of advanced breast cancer, and has also been evaluated in the adjuvant treatment setting. Although results from direct comparisons with tamoxifen are not expected for some time, data from the Intergroup Exemestane Study (IES), evaluating sequential therapy with tamoxifen for 2–3 years followed by exemestane for 2–3 years, compared with 5 years of tamoxifen therapy, have shown a significant advantage in favour of the sequential treatment option, with improvements in both disease-free and overall survival. Exemestane, in contrast to the non-steroidal agents, has weak androgenic activity. It was postulated that this might result in less adverse effects on bone.70 This provided some support for the potentially different mechanism of action of exemestane. However, in another biochemical study, exemestane was found to increase levels of bone turnover markers71 and in the Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) study, which compared the effects of all three clinically available aromatase inhibitors in postmenopausal women, no significant differences in the profile of biochemical markers of bone metabolism were seen. Of note, changes in parathyroid hormone were similar with all three agents, arguing against an anabolic effect of exemestane.
Results of a placebo-controlled trial of exemestane in early breast cancer have recently been published. In this study, 147 patients with low risk early breast cancer were randomized to receive treatment with exemestane 25 mg/day or placebo. Patients had a baseline DXA scan of the spine and hip, and follow-up assessments occurred annually. After 1 year, the BMD of patients in the exemestane group decreased by 2.17% and 2.72% at the spine and hip, respectively. However, bone loss in the placebo group was somewhat greater than expected, at 1.84% and 1.48% at the spine and hip, respectively. As a result, there was no significant difference between the two treatment groups at the lumbar spine, although the difference in hip BMD did reach statistical significance (p=0.024). None of the women were taking calcium or vitamin D supplements, and recent analysis has confirmed that many of these women were vitamin D deficient.74 In a 1-year follow up to the study after discontinuation of exemestane, the loss of BMD was partially reversed.
The effect of exemestane on markers of bone turnover was also assessed in this study. Exemestane was associated with significant increases in both markers of formation and resorption. In the exemestane group, levels of P1NP and CTX increased from baseline by 44% and 35%, respectively. However, levels of P1NP and CTX in the placebo group decreased by only 4% (p<0.001) and 5% (p=0.012), respectively.
The increase in bone resorption was consistent with the bone loss observed, while the increase in bone formation markers can be attributed to the coupling of bone formation to bone resorption.
Data from the bone sub-protocol of the IES study have recently become available.75 This study measured BMD and bone markers of resorption and formation in 206 patients at baseline, 6, 12 and 24 months. Patients who remained on tamoxifen showed no significant change from baseline in BMD. In patients who switched to exemestane, the mean rates of bone loss 6 months after tamoxifen cessation were 2.7% and 1.2% at the spine and hip, respectively. Thereafter, bone loss continued but at a slower rate of 0.5–1% per year. After 2 years, the change from baseline in BMD was 3.6% at the spine and 2.4% at the hip. Despite the more modest rate of bone loss seen in this bone sub-study, a significant increase in the incidence of fractures was observed in the IES study as a whole. With a median follow-up in all participants of 58 months and median exposure to exemestane of 30 months, 162 (7%) of patients in the exemestane group experienced a fracture compared with 115 (5%) patients in the tamoxifen group (odds ratio 1.45 [1.13–1.87]; p=0.003).
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2 comments:
very helpful article i like your work keep the good work like this thanks
Aicar , CJC 1295 with DAC
was no significant difference between the two treatment groups at the lumbar spine,
Aicar
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