What is anastrozole and how does it work?

What is Anastrozole and How Does It Work?

Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol in peripheral tissues, thereby suppressing estrogen biosynthesis in postmenopausal women. 1

Mechanism of Action

Anastrozole works by specifically inhibiting the aromatase enzyme, which is responsible for converting androgens to estrogens. 1 In postmenopausal women, this is the primary source of estrogen since ovarian production has ceased. 1 The drug achieves:

• Approximately 70% reduction in estradiol within 24 hours of the first dose 1
• Approximately 80% suppression after 14 days of daily dosing 1
• Suppression of serum estradiol to the lower limit of detection (3.7 pmol/L) at the standard 1 mg daily dose 1
• Sustained suppression for up to 6 days after stopping the medication 1

The drug demonstrates high selectivity—it does not affect cortisol or aldosterone secretion and requires no glucocorticoid or mineralocorticoid replacement therapy. 1

Critical Population Restriction

Anastrozole is contraindicated in premenopausal women because aromatization of adrenal androgens is not a significant source of estradiol in this population. 2, 1 The drug would not be expected to lower estradiol levels in premenopausal women and should never be used outside of clinical trials in this group. 2

Before initiating therapy, serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to confirm true postmenopausal status. 2

Clinical Applications in Postmenopausal Women

Anastrozole 1 mg daily is FDA-approved and guideline-recommended for:

• First-line treatment of hormone receptor-positive metastatic breast cancer, where it demonstrates superior efficacy to tamoxifen with longer time to progression 3, 1
• Adjuvant therapy for early-stage hormone receptor-positive breast cancer for 5 years 2, 4
• Risk reduction in postmenopausal women at increased breast cancer risk for 5 years 2
• Extended adjuvant therapy after 2-3 years of tamoxifen or following 5 years of tamoxifen 2, 4

Third-generation aromatase inhibitors like anastrozole are recommended over tamoxifen as first-line treatment based on their more favorable toxicity profile, though tamoxifen remains a valuable option. 3

Mandatory Pre-Treatment Evaluation

Before prescribing anastrozole, clinicians must:

• Measure baseline bone mineral density and assess fracture risk 2, 1
• Exclude severe osteoporosis (T-score < -4 or >2 vertebral fractures), which is an absolute contraindication 2
• Initiate comprehensive bone protection including calcium 1200 mg/day and vitamin D 400-600 IU/day 3, 2
• Encourage regular weight-bearing exercise 2

Critical Adverse Effect: Bone Loss

The most clinically significant adverse effect is increased fracture risk. In the landmark ATAC trial, anastrozole significantly increased fractures compared to tamoxifen (7.1% vs 4.1% after 37 months; OR 1.34,95% CI 1.22-1.57). 3 This occurs because:

• Anastrozole increases bone resorption markers and decreases spine and hip bone mineral density 3
• Approximately one-third of the excess fracture risk relates to the absence of tamoxifen's protective effect 3
• The fracture risk is restricted to the treatment period 4

Common Side Effects to Counsel Patients About

Patients must be informed of the following adverse effects:

• Joint stiffness and arthralgias (very common) 2
• Gastrointestinal disturbances (29-33% incidence, generally mild and transient) 5, 6
• Vasomotor symptoms including hot flushes 2
• Hypertension 2
• Dry eyes and vaginal dryness 2

Importantly, anastrozole causes significantly less weight gain than megestrol acetate and lacks the partial agonist activity of tamoxifen, avoiding potential endometrial proliferative effects. 7, 6

Pharmacokinetics

• Rapid absorption with maximum plasma concentrations within 2 hours under fasted conditions 1
• 40% protein binding in the therapeutic range 1
• Steady-state achieved in approximately 7 days with once-daily dosing 1
• Linear pharmacokinetics over the dose range of 1-20 mg 1

Food reduces the rate but not the overall extent of absorption, delaying time to maximum concentration from 2 to 5 hours. 1