Ovarian suppression as a result of chemotherapy in breast cancer
Cytotoxic chemotherapy used in the treatment of breast cancer can result in temporary amenorrhoea or, especially in older premenopausal women, irreversible damage to the ovarian tissues, leading to premature ovarian failure. Although there is no agreed definition of chemotherapy-induced ovarian failure, irreversible amenorrhoea lasting for several months (6–12 months) following chemotherapy and an elevated follicle-stimulating hormone seems to be widely accepted.25 An early menopause has been demonstrated in diseases other than breast
cancer where chemotherapy is used.
Few studies were identified specifically examining the effects of an early menopause associated with chemotherapy for breast cancer. However, in Hodgkin’s disease26,27 and lymphoma, studies have demonstrated that premature menopause is associated with reduced bone density especially in those who did not receive hormone replacement therapy (HRT).
In breast cancer, the changes in BMD resulting from a chemotherapy-induced menopause have been similar to those seen in other diseases. In a cohort study of 27 women with
early breast cancer who had received adjuvant chemotherapy at least 2 years before, 11 became amenorrhoeic.29 The amenorrhoeic women, who might have received up to 12 months of tamoxifen as part of their chemotherapy, had approximately a 14% reduction in their spine BMD compared with those who remained premenopausal. In a step-wise multiple regression
analysis, the only significant variable accounting for 28% of the variation in BMD was menopausal status.
A rapid and significant bone loss has been demonstrated in women with breast cancer treated with adjuvant chemotherapy. 30 In a prospective cohort study to determine the baseline predictors of ovarian failure in initially premenopausal women with breast cancer, 35 of 49 patients evaluated developed ovarian failure after 6 months of follow-up.31 At 6 months, the only significant predictors of ovarian failure in a multivariate model were age and alcohol intake in the past year.
Few studies have examined how the effects of an early menopause induced by chemotherapy can be abrogated, although the bisphosphonates are thought to play a role. Saarto et al reported on 113 women who were premenopausal before chemotherapy. 32 Of these, 38% became amenorrheoic in the first year, with a further 36% developing irregular menses and only 22% retaining regular menses. The likelihood of loss of regular menstruation increased with age. In this trial a total of 148 patients were randomised to receive oral clodronate or placebo (although the randomisation method lacked clarity and resulted in unequal numbers), and at 2 years of follow-up, overall bone loss was abrogated by the use of the bisphosphonate clodronate
at the lumbar spine (placebo: –5.9%, clodronate: –2.2%; p=0.005) and femoral neck (placebo: –2.0%, clodronate: +0.9%; p=0.017). Those women who became amenorrhoeic lost bone density in both treatment groups, although the magnitude of loss was significantly less if receiving clodronate (lumbar spine: 9.5% vs. 5.9%; femoral neck: 4.6% vs. 0.4%).
A small but well conducted randomised, controlled trial carried out in 53 women with an artificially induced menopause and a mean age of 47 years evaluated the effects of a
non-standard regimen of risedronate, 30 mg/day for 2 weeks, every 3 months.33 Of the 53 women, 36 had been pre-treated with tamoxifen. The BMD was maintained at the lumbar spine and hip sites in risedronate-treated women, compared with significant losses in the placebo group. At 2 years, the mean differences between the two treatment groups were 2.5% at the lumbar spine and 2.6% at the femoral neck. Both bone resorption and formation rates fell in the risedronate group compared with the placebo group. The BMD fell in a third year
of follow-up, i.e. when risedronate was stopped.
An analysis of a 12-month randomised, controlled trial (with a 12-month pre-planned extension) has been conducted in 87 women with breast cancer who had experienced a premature menopause a mean of 3.2 to 3.4 years earlier. In this analysis, risedronate 35 mg weekly was associated with increased BMD at the lumbar spine (+1.2%) and total hip (+1.3%), compared with mean losses in the placebo group (lumbar spine: –0.9%; total hip:–0.8%); the differences between the two groups were significant (p<0.01).34 Furthermore, bone markers (urinary N-telopeptide of type 1 collagen [NTX] and serum procollagen type 1 N-propeptide [P1NP]) were significantly reduced in the risedronate treatment group at 6 months in comparison with baseline.
Cytotoxic chemotherapy used in the treatment of breast cancer can result in temporary amenorrhoea or, especially in older premenopausal women, irreversible damage to the ovarian tissues, leading to premature ovarian failure. Although there is no agreed definition of chemotherapy-induced ovarian failure, irreversible amenorrhoea lasting for several months (6–12 months) following chemotherapy and an elevated follicle-stimulating hormone seems to be widely accepted.25 An early menopause has been demonstrated in diseases other than breast
cancer where chemotherapy is used.
Few studies were identified specifically examining the effects of an early menopause associated with chemotherapy for breast cancer. However, in Hodgkin’s disease26,27 and lymphoma, studies have demonstrated that premature menopause is associated with reduced bone density especially in those who did not receive hormone replacement therapy (HRT).
In breast cancer, the changes in BMD resulting from a chemotherapy-induced menopause have been similar to those seen in other diseases. In a cohort study of 27 women with
early breast cancer who had received adjuvant chemotherapy at least 2 years before, 11 became amenorrhoeic.29 The amenorrhoeic women, who might have received up to 12 months of tamoxifen as part of their chemotherapy, had approximately a 14% reduction in their spine BMD compared with those who remained premenopausal. In a step-wise multiple regression
analysis, the only significant variable accounting for 28% of the variation in BMD was menopausal status.
A rapid and significant bone loss has been demonstrated in women with breast cancer treated with adjuvant chemotherapy. 30 In a prospective cohort study to determine the baseline predictors of ovarian failure in initially premenopausal women with breast cancer, 35 of 49 patients evaluated developed ovarian failure after 6 months of follow-up.31 At 6 months, the only significant predictors of ovarian failure in a multivariate model were age and alcohol intake in the past year.
Few studies have examined how the effects of an early menopause induced by chemotherapy can be abrogated, although the bisphosphonates are thought to play a role. Saarto et al reported on 113 women who were premenopausal before chemotherapy. 32 Of these, 38% became amenorrheoic in the first year, with a further 36% developing irregular menses and only 22% retaining regular menses. The likelihood of loss of regular menstruation increased with age. In this trial a total of 148 patients were randomised to receive oral clodronate or placebo (although the randomisation method lacked clarity and resulted in unequal numbers), and at 2 years of follow-up, overall bone loss was abrogated by the use of the bisphosphonate clodronate
at the lumbar spine (placebo: –5.9%, clodronate: –2.2%; p=0.005) and femoral neck (placebo: –2.0%, clodronate: +0.9%; p=0.017). Those women who became amenorrhoeic lost bone density in both treatment groups, although the magnitude of loss was significantly less if receiving clodronate (lumbar spine: 9.5% vs. 5.9%; femoral neck: 4.6% vs. 0.4%).
A small but well conducted randomised, controlled trial carried out in 53 women with an artificially induced menopause and a mean age of 47 years evaluated the effects of a
non-standard regimen of risedronate, 30 mg/day for 2 weeks, every 3 months.33 Of the 53 women, 36 had been pre-treated with tamoxifen. The BMD was maintained at the lumbar spine and hip sites in risedronate-treated women, compared with significant losses in the placebo group. At 2 years, the mean differences between the two treatment groups were 2.5% at the lumbar spine and 2.6% at the femoral neck. Both bone resorption and formation rates fell in the risedronate group compared with the placebo group. The BMD fell in a third year
of follow-up, i.e. when risedronate was stopped.
An analysis of a 12-month randomised, controlled trial (with a 12-month pre-planned extension) has been conducted in 87 women with breast cancer who had experienced a premature menopause a mean of 3.2 to 3.4 years earlier. In this analysis, risedronate 35 mg weekly was associated with increased BMD at the lumbar spine (+1.2%) and total hip (+1.3%), compared with mean losses in the placebo group (lumbar spine: –0.9%; total hip:–0.8%); the differences between the two groups were significant (p<0.01).34 Furthermore, bone markers (urinary N-telopeptide of type 1 collagen [NTX] and serum procollagen type 1 N-propeptide [P1NP]) were significantly reduced in the risedronate treatment group at 6 months in comparison with baseline.
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