Aromatase inhibitors - Adjuvant breast cancer treatment associated with bone loss
Aromatase inhibitors are highly potent inhibitors of oestrogen production that suppress circulating oestradiol levels to almost undetectable levels. Possibly because there is no associated agonist effect, aromatase inhibition is a more effective treatment than tamoxifen. In particular, the third generation nonsteroidal (anastrozole and letrozole) and steroidal (exemestane) aromatase inhibitors inhibit the aromatase enzyme by 96–99%. Overall, aromatase inhibitors have a favourable side-effect profile but, owing to the known relationships between residual oestrogen levels and bone loss55 and also fracture risk, this associated marked reduction in oestradiol would be expected to have significant effects on bone physiology.
Clinical indications for aromatase inhibitors
Advances in adjuvant therapy have led to improvements in the long-term survival of women with early breast cancer; the 10-year probability of survival is now 80–85%. Tamoxifen has been the cornerstone of adjuvant endocrine therapy of breast cancer for several decades, a role that has largely been unchallenged until now.
Recently, the aromatase inhibitors have been shown to further reduce the risk of recurrence after a diagnosis of ER+ breast cancer, either when given in place of the previous standard of care (tamoxifen), or when administered in sequence after a few years of tamoxifen therapy. As a result of these trials, the aromatase inhibitors are now recommended in the adjuvant treatment setting, such that many women with breast cancer will be exposed to several, and possibly many years of treatment with an aromatase inhibitor.
Anastrozole and bone
Anastrozole has been shown to be at least as effective as tamoxifen in the treatment of metastatic breast cancer. In the adjuvant setting, the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial has demonstrated a significant advantage for anastrozole over tamoxifen. A recent update has shown not only an improvement in disease-free survival, but also a reduction in distant metastases.
The ATAC trial also demonstrated a favourable adverse event profile for anastrozole, compared with tamoxifen, with the exception of effects on the musculoskeletal system. In the anastrozole group, there were more musculoskeletal side effects and fractures, most frequently affecting the spine and fractures other than the hip and wrist. The incidence of all fractures in the 2007 update was 12% in the anastrozole group and 7.7% in the tamoxifen group (p<0.0001)64 (Table 1). To date, there has been no significant increase in fractures occurring at the hip, and the excess fracture incidence seen for anastrozole over tamoxifen during the 5-year treatment period appears to resolve on withdrawal of endocrine treatment. However, further data are required on the longterm effects of aromatase inhibitor treatment on bone health.
It is uncertain how much of the excess fracture risk can be attributed to the increase in bone turnover caused by anastrozole, as opposed to the loss of the bone protective effects of tamoxifen. Within the ATAC trial, a bone sub-protocol investigated 308 patients for changes in BMD and bone turnover markers.
Patients entering this part of the study had a DXA scan of the lumbar spine and hip, at baseline and after 12, 24 and 60 months on treatment. Bone turnover markers were also measured at baseline, 3, 6 and 12 months. A small increase in BMD at the spine and hip was observed in patients treated with tamoxifen, whereas anastrozole therapy was associated with a decrease in BMD at these sites. This was obvious at 1 year and further increased during the second year of therapy, with approximately a 2% loss of bone density annually (Figure 2). Over the course of the 5-year treatment programme, an average BMD loss of 7–8% was observed. Despite these changes, no patient with normal BMD at baseline developed osteoporosis.
The decrease in BMD observed in the ATAC trial was associated with an increase in bone remodelling, as demonstrated by an increase in markers of bone resorption and formation in the anastrozole group. There was a 26% increase in the bone resorption marker serum C-terminal telopeptide of type I collagen (CTX) and a 20% increase in the bone formation marker bone alkaline phosphatase (bone ALP). Conversely, tamoxifen therapy was associated with a decrease in markers of bone turnover.
Aromatase inhibitors are highly potent inhibitors of oestrogen production that suppress circulating oestradiol levels to almost undetectable levels. Possibly because there is no associated agonist effect, aromatase inhibition is a more effective treatment than tamoxifen. In particular, the third generation nonsteroidal (anastrozole and letrozole) and steroidal (exemestane) aromatase inhibitors inhibit the aromatase enzyme by 96–99%. Overall, aromatase inhibitors have a favourable side-effect profile but, owing to the known relationships between residual oestrogen levels and bone loss55 and also fracture risk, this associated marked reduction in oestradiol would be expected to have significant effects on bone physiology.
Clinical indications for aromatase inhibitors
Advances in adjuvant therapy have led to improvements in the long-term survival of women with early breast cancer; the 10-year probability of survival is now 80–85%. Tamoxifen has been the cornerstone of adjuvant endocrine therapy of breast cancer for several decades, a role that has largely been unchallenged until now.
Recently, the aromatase inhibitors have been shown to further reduce the risk of recurrence after a diagnosis of ER+ breast cancer, either when given in place of the previous standard of care (tamoxifen), or when administered in sequence after a few years of tamoxifen therapy. As a result of these trials, the aromatase inhibitors are now recommended in the adjuvant treatment setting, such that many women with breast cancer will be exposed to several, and possibly many years of treatment with an aromatase inhibitor.
Anastrozole and bone
Anastrozole has been shown to be at least as effective as tamoxifen in the treatment of metastatic breast cancer. In the adjuvant setting, the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial has demonstrated a significant advantage for anastrozole over tamoxifen. A recent update has shown not only an improvement in disease-free survival, but also a reduction in distant metastases.
The ATAC trial also demonstrated a favourable adverse event profile for anastrozole, compared with tamoxifen, with the exception of effects on the musculoskeletal system. In the anastrozole group, there were more musculoskeletal side effects and fractures, most frequently affecting the spine and fractures other than the hip and wrist. The incidence of all fractures in the 2007 update was 12% in the anastrozole group and 7.7% in the tamoxifen group (p<0.0001)64 (Table 1). To date, there has been no significant increase in fractures occurring at the hip, and the excess fracture incidence seen for anastrozole over tamoxifen during the 5-year treatment period appears to resolve on withdrawal of endocrine treatment. However, further data are required on the longterm effects of aromatase inhibitor treatment on bone health.
It is uncertain how much of the excess fracture risk can be attributed to the increase in bone turnover caused by anastrozole, as opposed to the loss of the bone protective effects of tamoxifen. Within the ATAC trial, a bone sub-protocol investigated 308 patients for changes in BMD and bone turnover markers.
Patients entering this part of the study had a DXA scan of the lumbar spine and hip, at baseline and after 12, 24 and 60 months on treatment. Bone turnover markers were also measured at baseline, 3, 6 and 12 months. A small increase in BMD at the spine and hip was observed in patients treated with tamoxifen, whereas anastrozole therapy was associated with a decrease in BMD at these sites. This was obvious at 1 year and further increased during the second year of therapy, with approximately a 2% loss of bone density annually (Figure 2). Over the course of the 5-year treatment programme, an average BMD loss of 7–8% was observed. Despite these changes, no patient with normal BMD at baseline developed osteoporosis.
The decrease in BMD observed in the ATAC trial was associated with an increase in bone remodelling, as demonstrated by an increase in markers of bone resorption and formation in the anastrozole group. There was a 26% increase in the bone resorption marker serum C-terminal telopeptide of type I collagen (CTX) and a 20% increase in the bone formation marker bone alkaline phosphatase (bone ALP). Conversely, tamoxifen therapy was associated with a decrease in markers of bone turnover.
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