Fractures tamoxifen

Selective estrogen receptor modulators (SERMs) are synthetic compounds with partially agonistic and partially antagonistic estrogenic properties. In bone, SERMs inhibit bone resorption via the mechanisms known for estrogens. Major SERMs are tamoxifen, a triphenylethylene compound, and raloxifene. In postmenopausal women, the latter has been shown to prevent bone loss and to reduce fracture risk by 40%. 

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. 

Exemestane is an irreversible aromatase inactivator that binds to the aromatase enzyme to block the production of estrogen from androgens. Exemestane is absorbed rapidly after oral administration, with a terminal half-life of 24 hours. The drug is eliminated primarily by the liver and feces, with less than 1% of the dose excreted unchanged in the urine. Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women who have had disease progression following tamoxifen therapy. Side effects include hot flashes, fatigue, osteoporosis/bone fractures, and flulike symptoms. 

In the Breast Cancer Prevention Trial (Fisher et al. 1998) a clinical survey aimed at determining the potential of tamoxifen for breast cancer prevention in women at increased risk, 13,338 pre- or postmenopausal women were monitored over 5 years. After randomization, women in the treatment group (n = 6681) were given a 20-mg daily dose of tamoxifen, while the remaining (n = 6707) received a placebo. Although the overall rate of fractures was about the same in both groups, tamoxifen-treated women sustained fewer hip, spine, and Colles fractures. Nevertheless, relevant data may have been biased, since in this trial there was an indiscriminate inclusion of pre- and postmenopausal women and no spinal radiographs were carried out. 

Raloxifene is a SERM devoid of stimulating effects on the uterus as is known from the initial studies (Delmas et al. 1997). Eliminating one of the major concerns raised by the experience gained with tamoxifen studies, both in prevention and adjuvant treatments, puts raloxifene in a place of privilege to be a rational alternative agent. At the same time it improves bone density, prevents osteoporosis and vertebral fracture, and reduces cardiovascular events in a subset of high-risk patients (Silverman et al. 2004). The evidences on the effects of raloxifene on the uterus are explained in detail in Chap. 10 of this book. 

Tamoxifen is commonly used in the treatment of breast carcinoma (1) the overall rates published for adverse effects vary very greatly, between 1 and 60% (2,3). It has also been used as a form of HRT to reduce bone loss and the incidence of fractures in high-risk cases (4). A combination of tamoxifen with ovarian suppression is as effective as the use of cytostatic drugs, and has been claimed to be better tolerated (5-7). 

More recently, another SERM, known as raloxifene (Evista), was developed. Raloxifene is similar to tamoxifen except that it blocks estrogen receptors on breast and uterine tissues and may therefore produce beneficial effects (inhibiting breast cancer, improving bone and cardiovascular function) without increasing the risk of endometrial cancers.30,51,57 Raloxifene is currently approved for treating osteoporosis, and the use of this drug is associated with increased vertebral bone density and a reduced risk of vertebral fractures.30,77... 

In the Breast Cancer Prevention Trial (P-1), initiated by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in 1992, more than 13 000 eligible women were randomized to tamoxifen 20 mg/day or placebo for 5 years (12). During 69 months of follow-up tamoxifen reduced the risk of both invasive and non-invasive cancer and reduced fractures of the hip, radius, and spine however, the rate of endometrial cancer increased (RR = 2.53 95% Cl = 1.35, 4.97), as did the frequency of vascular events. 

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, with its median follow-up of 68 months, has provided the best evidence to date that an adjuvant ana-strozole regimen is better tolerated (and more effective) than tamoxifen alone, but the problem remains that anastrozole reduces circulating estrogen, and that low estradiol concentrations cause reduced bone mineral density and hence an increased risk of fractures. In a substudy of the ATAC trial, the effects of prolonged long-term aroma-tase inhibitor therapy on bone mineral density have been examined in 197 patients, who took anastrozole 1 mg/day or tamoxifen 20 mg/day as adjuvant therapy for 5 years [45 ]. Anastrozole-treated women had reduced median bone mineral density compared with those who took tamoxifen, but it is striking that no patients with normal bone mineral density at the outset developed osteoporosis at 5 years. The real risks with anastrozole thus seem to be limited to women who have osteopenia at the start of treatment. 

Cooke AL, Metge C, Lix L, Prior HJ, Leslie WD. Tamoxifen use and osteoporotic fracture risk a population-based Analysis. J Qin Oncol 2008 26 5227-32. 

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