Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management

Aromatase inhibitors are widely used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. While the agents are associated with slightly improved survival outcomes when compared to tamoxifen alone, bone and musculoskeletal side effects are substantial and often lead to discontinuation of therapy. Ideally, the symptoms should be prevented or adequately treated. This review will focus on bone and musculoskeletal side effects of aromatase inhibitors, including osteoporosis, fractures, and arthralgias. Recent advances have been made in identifying potential mechanisms underlying these effects. Adequate management of symptoms may enhance patient adherence to therapy, thereby improving breast cancer-related outcomes

A randomised study comparing the effects of anastrozole (A), letrozole (L), exemestane (E) and tamoxifen (T) on coagulation.

Abstract Abstract #1132 Background:&amp;#x2028; Aromatase inhibitors (AIs) reduce circulating oestrogens and so should have either no or a positive effect on coagulation . This study compares the effects of the non-steroidal aromatase inhibitors, A and L and the steroidal inactivator, E on coagulation.&amp;#x2028; Patients and Methods:&amp;#x2028; This was an open, randomized pharmacodynamic study. Plasma coagulation factors were measured in 120 postmenopausal women with invasive ER +ve breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive upfront therapy with either:&amp;#x2028; 16 weeks of A, 16 weeks of L or 16 weeks of E.&amp;#x2028; Fasting blood samples were collected at entry and after 12 and 16 weeks of each drug. AI patients were then switched to T and further samples measured after 8 months on T.&amp;#x2028; Plasminogen activator inhibitor (PAI) antigen, von Willebrand's Factor (vWF) antigen, antithrombin III (AT111), protein C, protein S total, protein S free, activated protein C, resistance (APCR), factor VIII and fibrinogen were measured.&amp;#x2028; Results:&amp;#x2028; Results expressed as % change from baseline.&amp;#x2028; E vs A vs L&amp;#x2028; Protein C. E caused a significant fall compared to A and L (-15.75 (-21.48, -10.02) vs -3.80 (-10.77, 3.16) vs -3.63 (-10.50, 3.25)) respectively. p = 0.008.&amp;#x2028; ATIII. E caused a significant fall from baseline (-8.55 (-13.33, -3.79))&amp;#x2028; Protein S Free. E + A caused a significant increase from baseline (E 6.90 (1.98, 11.82), A 7.36 (1.37, 13.34).&amp;#x2028; Steroidal vs non-steroidal:&amp;#x2028; Protein C. A significantly greater fall was seen with E than A+L (-15.75 (-21.45, -10.05) vs -3.71 (-8.58, 1.15)) p = 0.002.&amp;#x2028; vWF A+L caused a significant increase from baseline (6.52 (0.66, 12.38) but this was not statistically different to E 5.02 (-1.88, 11.91)).&amp;#x2028; ATIII A significant decrease from baseline was seen with A + L, -4.54 (-8.64, -0.43) but no difference from E 8.55 (13.31, -3.70) p=0.21.&amp;#x2028; Protein S Free There was a significant increase from baseline in both groups (A+L: 5.70 (1.47, 9.92), E: 6.90 (1.98, 11.81), but no difference between the groups p=0.72.&amp;#x2028; T effect:&amp;#x2028; AT111 and protein C levels fell significantly on T whereas protein S free increased on T. Prior A, E or L had no significant impact on post-tamoxifen results.&amp;#x2028; Conclusions:&amp;#x2028; No significant differences in any coagulation factors were seen between A and L&amp;#x2028; E caused a significant fall in protein C and ATIII.&amp;#x2028; The non-steroidal AIs caused a significant increase in vWF.&amp;#x2028; T caused a significant fall in protein C and ATIII and a significant increase in protein S free.&amp;#x2028; No AI significantly influenced post-tamoxifen results.&amp;#x2028; These drugs have significant effects on coagulation which helps to explain their clinical effects on thrombotic and thromboembolic disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1132.</jats:p

A randomised study comparing the effects of anastrozole and letrozole on lipid metabolism.

Abstract Abstract #1152 Background:&amp;#x2028; Aromatase inhibitors (AIs) reduce circulating oestrogen which may have a detrimental effect on lipid metabolism. Letrozole (L) decreases circulating oestrogen levels to a greater degree than anastrozole (A). This study compares the effects of adjuvant anastrozole and letrozole on lipid metabolism.&amp;#x2028; Patients and Methods:&amp;#x2028; This was an open, randomised pharmacodynamic study. Plasma lipids were measured in a subset of 57 out of 182 postmenopausal women with invasive ER positive breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive either&amp;#x2028; · 12 weeks of L followed by 12 weeks of A (L→A) or&amp;#x2028; · 12 weeks of A followed by 12 weeks of L (A→L).&amp;#x2028; Fasting blood and urine samples were collected at the same time of day and the same day at entry and after 12 weeks of each drug.&amp;#x2028; · 29 had no prior tamoxifen and&amp;#x2028; · 27 had received tamoxifen.&amp;#x2028; The following lipoproteins were measured:&amp;#x2028; - Triglyceride - HDL&amp;#x2028; - Cholesterol - ApoA1&amp;#x2028; - ApoB&amp;#x2028; - Cholesterol&amp;#x2028; - cLDL&amp;#x2028; HDL and ApoA1 are cardioprotective whereas ↑ levels of the others are associated with an ↑ risk of coronary artery disease.&amp;#x2028; Results:&amp;#x2028; (Expressed as absolute changes +/- 95% CI)&amp;#x2028; Patients who stopped tamoxifen &amp;gt;12 weeks prior to trial entry were considered tamoxifen free. Patients who had stopped tamoxifen &amp;lt;12 weeks prior to trial entry were considered to have tamoxifen in their system at trial entry.&amp;#x2028; A vs L: &amp;#x2028; There were no significant differences detected between A and L.&amp;#x2028; A vs L in tamoxifen vs no tamoxifen groups:&amp;#x2028; Triglycerides. Both A and L resulted in a significant decrease in triglycerides in patients who had tamoxifen in their systems, A = -0.02 (-0.24, 0.20) and L = 0.08 (-0.13, 0.29) vs those with no prior tamoxifen A = 0.51 (0.35, 0.68) and L = 0.56 (0.39, 0.72). A p = 0.0003 and L p = 0.001 respectively.&amp;#x2028; ApoB. Both A and L resulted in a significant decrease in ApoB in patients who had tamoxifen in their systems, A = 0.78 (0.64, 0.91) and L = 0.84 (0.71, 0.97) vs those with no prior tamoxifen A = 0.92 (0.82, 1.02) and L = 0.91 (0.80, 1.01). p = 0.03 for both drugs.&amp;#x2028; HDL. A resulted in a significant increase in HDL in patients who had tamoxifen in their systems 1.68 (1.49, 1.86) vs those with no prior tamoxifen 1.38 (1.24, 1.53) p = 0.02.&amp;#x2028; There were no significant changes for any other variables measured.&amp;#x2028; Conclusions:&amp;#x2028; There were no significant differences between letrozole and anastrozole in their effects on lipids.&amp;#x2028; Patients who had recently completed tamoxifen and commenced anastrozole or letrozole showed beneficial changes in their lipid profile compared to patients with no tamoxifen in their systems. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1152.</jats:p

A randomised study of the effects of anastrozole (A), letrozole (L) and exemestane (E) on bone turnover.

Abstract Abstract #1145 Background:&amp;#x2028; Aromatase inhibitors (AIs) reduce circulating oestrogen which increases bone turnover. L decreases circulating oestrogen levels to a greater degree than A. This study compares the effects of the non-steroidal aromatase inhibitors, A and L and the steroidal inactivator, E on bone turnover.&amp;#x2028; Patients and Methods:&amp;#x2028; This was an open, randomized pharmacodynamic study. Bone turnover markers were measured in 162 postmenopausal women with invasive ER +ve breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive either:&amp;#x2028; 16 weeks of A, 16 weeks of L or 16 weeks of E&amp;#x2028; Fasting blood and urine samples were collected at entry and after 12 and 16 weeks of each drug. Bone remodelling releases breakdown products of type 1 collagen including the terminal peptide fragments N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx). An increase in these indicates bone resorption. Increases in type 1 pro-collagen peptides (N-terminal – PINP) and bone specific alkaline phosphatase (ALP) indicate bone formation. These were measured as was parathyroid hormone (PTH) which is an indirect measure of overall bone turnover.&amp;#x2028; Results:&amp;#x2028; A vs E vs L&amp;#x2028; A, E and L significantly increased the bone turnover markers - PINP, CTX and bone ALP.&amp;#x2028; E showed a greater change in bone turnover but there were no significant differences between the drugs.&amp;#x2028; &amp;#x2028; &amp;#x2028; &amp;#x2028; E resulted in a greater increase in PINP and uNTX compared to the non-steroidal AIs however these were of borderline significance.&amp;#x2028; PINP, CTX and bone ALP all have significantly higher than zero percentage changes, regardless of drug or drug type.&amp;#x2028; Conclusions:&amp;#x2028; AIs cause a significant increase in both bone breakdown and bone formation.&amp;#x2028; There is no evidence to suggest E has less effects on bone turnover than A or L. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1145.</jats:p

Preventive effect of risedronate on bone loss and frailty fractures in elderly women treated with anastrozole for early breast cancer.

The aim of this study was to assess the effect of adjuvant anastrozole, alone or associated with risedronate, on BMD and bone fracture risk in women more than 70 years old with hormone receptor-positive early breast cancer (EBC). In a group of 51 elderly women (aged 76.4 \ub1 5.0 years) considered for adjuvant aromatase inhibitors for EBC, 24 patients with T-scores 65 -2 and no prevalent fractures received anastrozole 1 mg/day (group A), and 27 patients with T-scores < -2, or with T-scores 65 -2 and prevalent fractures (group B), received anastrozole (1 mg/day) plus risedronate (35 mg/week). Both groups received supplementation with 1 g calcium carbonate and 800 IU vitamin D per day. Differences in BMD and frailty fractures were evaluated after 1 and 2 years. In group A, significant decreases in BMD were observed in the lumbar spine (\u394 BMD, -0.030 \ub1 0.04 g/cm(2), P < 0.05), femoral neck (\u394 BMD, -0.029 \ub1 0.05 g/cm(2), P < 0.05), and trochanter (\u394 BMD, -0.026 \ub1 0.03 g/cm(2), P < 0.01) after 2 years. The greatest percent reduction in height (Hpr) emerged in the thoracic spine (3.6 \ub1 2.4%, P < 0.01), although only one incident vertebral fracture was observed. In group B, BMD increased in the lumbar spine (\u394 BMD, 0.038 \ub1 0.04, P < 0.001), although no significant changes were seen in the hip regions. The decline in Hpr was negligible (about 1%). No incident fractures were observed at follow-up. In conclusion, anastrozole treatment for EBC in elderly women seems to have only mild negative effects on the femoral bone. Risedronate makes the use of anastrozole safer, even for osteopenic or osteoporotic elderly patients