Management of Anastrozole-Induced Bone Loss in Breast Cancer
Introduction The aim of this multicenter, phase III, prospective open label clinical trial was to investigate the effect of risedronate (R) on bone mineral density (BMD) in postmenopausal, early breast cancer (BC) patients scheduled to receive anastrozole (A).
Methods Pre-treatment BMD of 213 patients with hormone receptor-positive BC was evaluated at lumbar spine (LS) and hip (HP). Patients were categorized according to their baseline BMD T-score as being at low, moderate and high risk of osteoporosis. Low risk patients received anastrozole only (A), moderate risk were randomized to anastrozole +/− risedronate (A+/−R) administration and high risk patients received anastrozole + risedronate (A+R). Anastrozole was given at a dosage of 1 mg/day while oral risedronate was given at 35 mg/week. BMD was then assessed at 12 and 24 months. All patients received daily supplements of calcium (1000 mg/day) and vitamin D (400 IU/day).
Results At 24 months, in the moderate risk group, treatment with A+R resulted in a significant increase in BMD at LS and HP compared to treatment with A only (5.7% v −1.5%, Wilcoxon test P = 0.006, and 1.6% v −3.9% Wilcoxon test P = 0.037, respectively), while no significant difference was found at 12 months; 24.3% of the patients moved to normal BMD region. In the high risk group, a significant increase for LS was detected both at 12 and 24 months (6.3% and 6.6%, P < 0.001) but not for HP; BMD in 14% of patients improved to the osteopenic region. In the low risk group, a significant decrease of BMD was detected at 12 months for LS and HP (−5.3% P < 0.001 and −2.4% P < 0.001, respectively,); at 24 months, a significant decrease of BMD was detected only for LS (−2.5%, P < 0.001). However, 22% of patients became osteopenic and only 4% became osteoporotic.
Conclusions The addition of oral risedronate in post-menopausal breast cancer patients receiving anastrozole has a favorable effect on BMD. Patients with pre-treatment osteopenic to osteoporotic status should be treated with a combination of both therapies in order to avoid bone loss induced by aromatase inhibition. Patients with normal BMD before starting treatment with anastrozole have a very low risk to develop osteoporosis.
More than 70% of breast cancer patients develop endocrine-responsive disease with estrogen receptor (ER)-positive or progesterone receptor-positive tumors or both and require endocrine treatment with either estrogen blockage or ablation. On the other hand, it is well known that estrogens have an indirect and positive effect on bone metabolism by stimulating the production of several cytokines acting either as inhibitors of osteoclastogenesis or as antireceptive agents leading active osteoclasts to apoptosis. Therefore, the depletion of estrogens in patients with endocrine-responsive breast cancer leads to increased bone resorption and finally osteoporosis occurs, resulting in increased risk for bone fractures.
The introduction of aromatase inhibitors (AIs) during the last decade has opened new horizons in the successful treatment of ER-positive breast cancer. Clinical trials established the role of AIs in the adjuvant therapy of postmenopausal women with hormone-responsive breast cancer in upfront, switch, and sequential treatment settings and this is reflected by international guidelines such as those of the American Society of Clinical Oncology, St. Gallen, the National Comprehensive Cancer Network, and others.
However, various clinical studies demonstrated that estrogen deprivation caused by AI administration has a serious negative effect on bone health. Bone mineral density (BMD) rapidly decreases with a consequent high risk of skeletal fragility due to aromatase inhibitor-associated bone loss (AIBL). For the prevention of this adverse event, antiresoptive agents such as bisphosphonates (BPs) are used in combination with AIs.
BPs have a high affinity for hydroxyapatite, bind directly to mineralized bone, and enable the bone to be resistant to endogenous phosphatases. On osteoclast stimulation of bone resorption, the BP is released and internalized by the osteoclasts, interfering with osteoclast formation, function, and survival. Various compounds of BPs, available for either oral or intravenous administration, can have a beneficial effect on tumor-induced osteolysis, thereby minimizing the destructive consequences of estrogen deficiency-associated osteoporosis. However, oral BPs can be administered at home in weekly or monthly formulations, offering convenience for patients and, in this respect, could be the ideal treatment for the prevention of skeletal complications in early breast cancer patients with no evidence of metastatic spread to bones.
Arimidex Bone Mass Index and Oral Bisphosphonates (ARBI) is a phase III, multicenter, open-label clinical trial conducted by the Hellenic Society of Breast Surgeons. The primary aims of this study were to investigate the effect of risedronate on BMD changes from baseline in postmenopausal, early breast cancer patients receiving anastrozole with follow-up from baseline to 24 months and to evaluate the effect of anastrozole monotherapy on bone mass in a group of patients with normal BMD before starting treatment.
Abstract and Introduction
Abstract
Introduction The aim of this multicenter, phase III, prospective open label clinical trial was to investigate the effect of risedronate (R) on bone mineral density (BMD) in postmenopausal, early breast cancer (BC) patients scheduled to receive anastrozole (A).
Methods Pre-treatment BMD of 213 patients with hormone receptor-positive BC was evaluated at lumbar spine (LS) and hip (HP). Patients were categorized according to their baseline BMD T-score as being at low, moderate and high risk of osteoporosis. Low risk patients received anastrozole only (A), moderate risk were randomized to anastrozole +/− risedronate (A+/−R) administration and high risk patients received anastrozole + risedronate (A+R). Anastrozole was given at a dosage of 1 mg/day while oral risedronate was given at 35 mg/week. BMD was then assessed at 12 and 24 months. All patients received daily supplements of calcium (1000 mg/day) and vitamin D (400 IU/day).
Results At 24 months, in the moderate risk group, treatment with A+R resulted in a significant increase in BMD at LS and HP compared to treatment with A only (5.7% v −1.5%, Wilcoxon test P = 0.006, and 1.6% v −3.9% Wilcoxon test P = 0.037, respectively), while no significant difference was found at 12 months; 24.3% of the patients moved to normal BMD region. In the high risk group, a significant increase for LS was detected both at 12 and 24 months (6.3% and 6.6%, P < 0.001) but not for HP; BMD in 14% of patients improved to the osteopenic region. In the low risk group, a significant decrease of BMD was detected at 12 months for LS and HP (−5.3% P < 0.001 and −2.4% P < 0.001, respectively,); at 24 months, a significant decrease of BMD was detected only for LS (−2.5%, P < 0.001). However, 22% of patients became osteopenic and only 4% became osteoporotic.
Conclusions The addition of oral risedronate in post-menopausal breast cancer patients receiving anastrozole has a favorable effect on BMD. Patients with pre-treatment osteopenic to osteoporotic status should be treated with a combination of both therapies in order to avoid bone loss induced by aromatase inhibition. Patients with normal BMD before starting treatment with anastrozole have a very low risk to develop osteoporosis.
Introduction
More than 70% of breast cancer patients develop endocrine-responsive disease with estrogen receptor (ER)-positive or progesterone receptor-positive tumors or both and require endocrine treatment with either estrogen blockage or ablation. On the other hand, it is well known that estrogens have an indirect and positive effect on bone metabolism by stimulating the production of several cytokines acting either as inhibitors of osteoclastogenesis or as antireceptive agents leading active osteoclasts to apoptosis. Therefore, the depletion of estrogens in patients with endocrine-responsive breast cancer leads to increased bone resorption and finally osteoporosis occurs, resulting in increased risk for bone fractures.
The introduction of aromatase inhibitors (AIs) during the last decade has opened new horizons in the successful treatment of ER-positive breast cancer. Clinical trials established the role of AIs in the adjuvant therapy of postmenopausal women with hormone-responsive breast cancer in upfront, switch, and sequential treatment settings and this is reflected by international guidelines such as those of the American Society of Clinical Oncology, St. Gallen, the National Comprehensive Cancer Network, and others.
However, various clinical studies demonstrated that estrogen deprivation caused by AI administration has a serious negative effect on bone health. Bone mineral density (BMD) rapidly decreases with a consequent high risk of skeletal fragility due to aromatase inhibitor-associated bone loss (AIBL). For the prevention of this adverse event, antiresoptive agents such as bisphosphonates (BPs) are used in combination with AIs.
BPs have a high affinity for hydroxyapatite, bind directly to mineralized bone, and enable the bone to be resistant to endogenous phosphatases. On osteoclast stimulation of bone resorption, the BP is released and internalized by the osteoclasts, interfering with osteoclast formation, function, and survival. Various compounds of BPs, available for either oral or intravenous administration, can have a beneficial effect on tumor-induced osteolysis, thereby minimizing the destructive consequences of estrogen deficiency-associated osteoporosis. However, oral BPs can be administered at home in weekly or monthly formulations, offering convenience for patients and, in this respect, could be the ideal treatment for the prevention of skeletal complications in early breast cancer patients with no evidence of metastatic spread to bones.
Arimidex Bone Mass Index and Oral Bisphosphonates (ARBI) is a phase III, multicenter, open-label clinical trial conducted by the Hellenic Society of Breast Surgeons. The primary aims of this study were to investigate the effect of risedronate on BMD changes from baseline in postmenopausal, early breast cancer patients receiving anastrozole with follow-up from baseline to 24 months and to evaluate the effect of anastrozole monotherapy on bone mass in a group of patients with normal BMD before starting treatment.