Breast cancer treatments associated with ovarian suppression
There are a number of ways in which women treated for breast cancer may have premature ovarian suppression and hence be at increased risk of osteoporosis and fractures. The section that follows examines each in turn, with the recommendations for assessment and management, drawn from a systematic review of the literature.
Ovarian suppression as a result of gonadotrophin-releasing hormone agonists Gonadotrophin-releasing hormone (GnRH) agonists are a group of compounds (including goserelin, nafarelin, triptorelin and leuprolide) that lead to super stimulation of the GnRH receptors on the anterior pituitary. After an initial increase in gonadotrophin secretion, this leads to down-regulation of receptor activity with suppression of gonadotrophin secretion and reversible inhibition of gonadal activity. These agents have well accepted roles in the management of benign conditions such as endometriosis, uterine fibroids, and ovarian regulation prior to ovulation induction. In
oncology, they are used in prostate cancer and in the management of breast cancer in premenopausal women.
Most of the information regarding the effect of these agents on the skeleton is derived from studies in premenopausal women with benign indications. Here, there is a consistent induction of a menopause-like state, with typical climacteric symptoms and a rapid increase in bone turnover leading to a reduction in bone mass. Most studies demonstrate a consistent loss of 4–5% in
lumbar spine BMD over the first 6 months of therapy. In most benign indications for GnRH therapy, treatment is limited to a few months and so information about longer-term bone loss
and associated fracture incidence is not available. Following cessation of therapy, there is resumption of ovarian function and restoration of much of the lost bone. Several therapies have been shown to reduce the bone loss associated with GnRH inhibitor therapy in premenopausal women. These include oestrogen replacement, tibolone, raloxifene, etidronate and zoledronic acid.
GnRH inhibition is used to induce reversible ovarian suppression in premenopausal women with oestrogen receptorpositive (ER+) breast cancer. There is little information regarding the skeletal effect of GnRH inhibition in breast cancer but it seems reasonable to assume the same effects as in underlying benign disease states, due to similar early effects on the skeleton. Importantly, in breast cancer, the treatment is continued for several years (usually 2–5 years) and so the effect on the skeleton would be expected to be more marked than that observed in the benign indications, where treatment duration is limited.
In a subset of patients from a large study (the ZEBRA study) of 1640 women receiving goserelin as part of early breast cancer treatment, bone density was measured in 53 women treated with goserelin and compared with 43 women treated with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy.
19 At the end of the first year, the goserelin-treated group had lost 8.2% of bone density from the lumbar spine and 4.5% from the femoral neck. The lumbar spine loss associated with goserelin was significantly greater than that observed with chemotherapy (4.5%), but the femoral loss was similar in the two treatment groups. After 2 years, bone loss was significantly greater in the goserelin group at both measurement sites compared with those
receiving chemotherapy (spine: –10.5% vs. –6.5%; femoral neck: –6.4% vs. –4.5%). After the second year of therapy, goserelin was stopped, as required by the protocol. Menses returned in 72.7% of goserelin recipients upon cessation of therapy, and this was associated with a partial recovery of bone density at 3 years, whereas amenorrhoea was permanent in the majority of CMF recipients (76.5% of patients at 3 years). As a result, no significant differences in BMD were observed between the goserelin group and those receiving chemotherapy at the 3–year assessment (spine: –6.2% vs. –7.2%; femoral neck: –3.1% vs. –4.6%).
In a small, randomised, controlled trial, bone density results were evaluated in 13 patients treated with goserelin alone, and compared with 14 patients receiving goserelin plus tamoxifen, 18 patients receiving tamoxifen alone, and 21 patients not receiving any endocrine therapy.20 At the end of the 2-year treatment period, the goserelin treatment group had lost 5.0% of their total body bone density compared with 0.3% in the group receiving no endocrine therapy. The bone loss was reduced by the co-administration of tamoxifen; patients treated with goserelin plus tamoxifen experienced a bone loss of 1.4%. Following cessation of goserelin, there was a 1.5% recovery of bone mass 1 year after treatment was finished.
More recently, a larger study investigating the combination of goserelin and tamoxifen showed rapid bone loss during the first year, which continued at a slower rate in years 2 and 3 to give an estimated loss of 11.6% in lumbar spine bone density at the end of 3 years.21 This compared with an estimated loss at 3 years of 17.3% if goserelin was combined with the aromatase inhibitor anastrozole. Bone loss in both of these groups was prevented by the administration of zoledronic acid; this was initially given at a dose of 8 mg by intravenous infusion every 6 months, but early in the study the dose was reduced to 4 mg every 6 months. Similar but less marked changes were seen in the proximal femur. Partial recovery was seen on cessation of goserelin and endocrine treatment, but significant bone loss persisted at 5 years. None of these studies were of sufficient size or had sufficient follow up to allow any insight into fracture rates during or following GnRH therapy. Furthermore, it must be remembered that this treatment is primarily aimed at premenopausal women that are likely to start off with a low absolute fracture risk.23 However, comparison with the findings in older men treated with GnRH agonists for prostate cancer, where similar changes in bone density are seen, would indicate that absolute fracture
risk will be increased following this treatment
There are a number of ways in which women treated for breast cancer may have premature ovarian suppression and hence be at increased risk of osteoporosis and fractures. The section that follows examines each in turn, with the recommendations for assessment and management, drawn from a systematic review of the literature.
Ovarian suppression as a result of gonadotrophin-releasing hormone agonists Gonadotrophin-releasing hormone (GnRH) agonists are a group of compounds (including goserelin, nafarelin, triptorelin and leuprolide) that lead to super stimulation of the GnRH receptors on the anterior pituitary. After an initial increase in gonadotrophin secretion, this leads to down-regulation of receptor activity with suppression of gonadotrophin secretion and reversible inhibition of gonadal activity. These agents have well accepted roles in the management of benign conditions such as endometriosis, uterine fibroids, and ovarian regulation prior to ovulation induction. In
oncology, they are used in prostate cancer and in the management of breast cancer in premenopausal women.
Most of the information regarding the effect of these agents on the skeleton is derived from studies in premenopausal women with benign indications. Here, there is a consistent induction of a menopause-like state, with typical climacteric symptoms and a rapid increase in bone turnover leading to a reduction in bone mass. Most studies demonstrate a consistent loss of 4–5% in
lumbar spine BMD over the first 6 months of therapy. In most benign indications for GnRH therapy, treatment is limited to a few months and so information about longer-term bone loss
and associated fracture incidence is not available. Following cessation of therapy, there is resumption of ovarian function and restoration of much of the lost bone. Several therapies have been shown to reduce the bone loss associated with GnRH inhibitor therapy in premenopausal women. These include oestrogen replacement, tibolone, raloxifene, etidronate and zoledronic acid.
GnRH inhibition is used to induce reversible ovarian suppression in premenopausal women with oestrogen receptorpositive (ER+) breast cancer. There is little information regarding the skeletal effect of GnRH inhibition in breast cancer but it seems reasonable to assume the same effects as in underlying benign disease states, due to similar early effects on the skeleton. Importantly, in breast cancer, the treatment is continued for several years (usually 2–5 years) and so the effect on the skeleton would be expected to be more marked than that observed in the benign indications, where treatment duration is limited.
In a subset of patients from a large study (the ZEBRA study) of 1640 women receiving goserelin as part of early breast cancer treatment, bone density was measured in 53 women treated with goserelin and compared with 43 women treated with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy.
19 At the end of the first year, the goserelin-treated group had lost 8.2% of bone density from the lumbar spine and 4.5% from the femoral neck. The lumbar spine loss associated with goserelin was significantly greater than that observed with chemotherapy (4.5%), but the femoral loss was similar in the two treatment groups. After 2 years, bone loss was significantly greater in the goserelin group at both measurement sites compared with those
receiving chemotherapy (spine: –10.5% vs. –6.5%; femoral neck: –6.4% vs. –4.5%). After the second year of therapy, goserelin was stopped, as required by the protocol. Menses returned in 72.7% of goserelin recipients upon cessation of therapy, and this was associated with a partial recovery of bone density at 3 years, whereas amenorrhoea was permanent in the majority of CMF recipients (76.5% of patients at 3 years). As a result, no significant differences in BMD were observed between the goserelin group and those receiving chemotherapy at the 3–year assessment (spine: –6.2% vs. –7.2%; femoral neck: –3.1% vs. –4.6%).
In a small, randomised, controlled trial, bone density results were evaluated in 13 patients treated with goserelin alone, and compared with 14 patients receiving goserelin plus tamoxifen, 18 patients receiving tamoxifen alone, and 21 patients not receiving any endocrine therapy.20 At the end of the 2-year treatment period, the goserelin treatment group had lost 5.0% of their total body bone density compared with 0.3% in the group receiving no endocrine therapy. The bone loss was reduced by the co-administration of tamoxifen; patients treated with goserelin plus tamoxifen experienced a bone loss of 1.4%. Following cessation of goserelin, there was a 1.5% recovery of bone mass 1 year after treatment was finished.
More recently, a larger study investigating the combination of goserelin and tamoxifen showed rapid bone loss during the first year, which continued at a slower rate in years 2 and 3 to give an estimated loss of 11.6% in lumbar spine bone density at the end of 3 years.21 This compared with an estimated loss at 3 years of 17.3% if goserelin was combined with the aromatase inhibitor anastrozole. Bone loss in both of these groups was prevented by the administration of zoledronic acid; this was initially given at a dose of 8 mg by intravenous infusion every 6 months, but early in the study the dose was reduced to 4 mg every 6 months. Similar but less marked changes were seen in the proximal femur. Partial recovery was seen on cessation of goserelin and endocrine treatment, but significant bone loss persisted at 5 years. None of these studies were of sufficient size or had sufficient follow up to allow any insight into fracture rates during or following GnRH therapy. Furthermore, it must be remembered that this treatment is primarily aimed at premenopausal women that are likely to start off with a low absolute fracture risk.23 However, comparison with the findings in older men treated with GnRH agonists for prostate cancer, where similar changes in bone density are seen, would indicate that absolute fracture
risk will be increased following this treatment
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