What is Letrozole and How Does It Work?
Letrozole, sold under the brand name Femara, is a type of hormone therapy known as an aromatase inhibitor (AI) [1.5.9]. It is primarily used to treat hormone receptor-positive (HR+) breast cancer in postmenopausal women [1.2.4]. The medication works by blocking the enzyme aromatase, which in turn suppresses the body's production of estrogen [1.3.9]. Since many breast cancers use estrogen to grow, lowering these hormone levels can help stop or slow the cancer's progression.
Beyond oncology, letrozole is also used off-label to treat certain types of infertility [1.4.7]. In this context, it is used for a much shorter duration—typically just for a few cycles—so the long-term risks discussed below are not the primary concern for fertility patients.
Standard Duration of Letrozole Therapy
The definition of "too long" is contextual and depends on the treatment plan established by an oncologist. For treating primary breast cancer, letrozole is typically taken daily for five to ten years [1.3.2, 1.3.4, 1.3.5]. This extended, or adjuvant, therapy is designed to reduce the risk of cancer recurrence [1.2.4]. The decision to continue therapy beyond five years depends on an individual's risk of recurrence versus their tolerance for the side effects [1.3.7].
Key Long-Term Risks of Extended Letrozole Use
While letrozole is a life-saving medication for many, its long-term use is associated with several significant side effects due to prolonged estrogen deprivation [1.2.4].
Musculoskeletal Effects: Bone Density Loss and Joint Pain
The most well-documented long-term side effects involve the musculoskeletal system.
- Bone Loss (Osteoporosis): Letrozole can significantly decrease bone mineral density over time, leading to osteopenia (weak bones) or osteoporosis [1.2.1, 1.2.3]. This thinning of the bones increases the risk of fractures [1.4.7]. In clinical trials, bone fractures occurred in up to 22% of patients on letrozole [1.2.1].
- Joint and Muscle Pain (Arthralgia and Myalgia): Joint pain is a very common side effect, affecting almost half of women taking aromatase inhibitors [1.6.4]. The pain can occur in the hands, wrists, feet, knees, and back, and is often a reason why patients consider stopping treatment [1.2.4, 1.6.4]. While the pain does not cause permanent joint damage, it can severely impact quality of life [1.6.4].
Cardiovascular Health Concerns
Extended letrozole therapy can also impact cardiovascular health.
- High Cholesterol: Letrozole is known to increase cholesterol levels in the blood [1.2.1, 1.4.1]. One study showed hypercholesterolemia in 53% of patients [1.2.1]. This requires regular monitoring by a doctor, who may prescribe medication to manage it [1.4.1].
- Cardiovascular Events: Compared to another hormone therapy, tamoxifen, aromatase inhibitors are associated with an increased risk of heart failure and cardiovascular mortality [1.6.1]. While letrozole has a lower risk of blood clots than tamoxifen, it has a higher incidence of cardiac events and high blood pressure [1.5.7, 1.2.2].
Genitourinary and Sexual Health Side Effects
The lack of estrogen also affects genitourinary health, mimicking menopausal symptoms [1.2.4].
- Vaginal Dryness: Vaginal dryness, irritation, and bleeding are common side effects [1.2.1]. This can lead to pain during intercourse and affect sexual health.
- Urinary Tract Infections (UTIs): Some patients may experience an increased frequency of UTIs [1.2.8].
Comparison: Letrozole vs. Other Hormone Therapies
Letrozole's side effect profile differs from other common hormone therapies like Anastrozole (another AI) and Tamoxifen (a SERM).
| Side Effect | Letrozole (AI) | Anastrozole (AI) | Tamoxifen (SERM) |
|---|---|---|---|
| Bone Density Loss | Higher Risk [1.2.3] | Higher Risk [1.6.9] | Lower Risk / Protective [1.5.4] |
| Joint/Muscle Pain | Common (up to 48%) [1.5.2] | Common (up to 48%) [1.5.2] | Less Common [1.6.2] |
| Hot Flashes | Common (32.5%) [1.5.2] | Common (32.3%) [1.5.2] | Very Common (35%) [1.6.2] |
| Risk of Blood Clots | Lower Risk [1.5.7] | Lower Risk [1.5.5] | Higher Risk [1.5.7] |
| Risk of Endometrial Cancer | Lower Risk [1.5.7] | Lower Risk [1.5.5] | Higher Risk [1.5.7] |
| High Cholesterol | Increased Risk [1.5.7] | Increased Risk [1.5.4] | Lipid-lowering effect [1.5.4] |
Managing the Risks of Long-Term Treatment
Living with the side effects of long-term letrozole use requires a proactive partnership with a healthcare team. Management strategies include:
- Regular Monitoring: Blood tests to check cholesterol and liver function, as well as regular blood pressure checks, are essential [1.4.1, 1.4.6].
- Bone Health Management: Baseline and periodic DEXA scans are used to monitor bone mineral density [1.4.5, 1.4.6]. Doctors often recommend calcium and vitamin D supplements [1.4.5]. For significant bone loss, medications like bisphosphonates may be prescribed [1.4.4].
- Lifestyle Adjustments: Weight-bearing exercise, such as walking, can help maintain bone strength and joint flexibility [1.4.2, 1.4.3]. A healthy diet and maintaining a healthy weight are also crucial [1.4.2].
- Symptom Relief: Over-the-counter pain relievers can help with joint pain after consulting a doctor [1.2.2]. For vaginal dryness, moisturizers or lubricants can provide relief.
Conclusion: Balancing Efficacy and Side Effects
Taking letrozole for an extended period is a proven strategy for reducing breast cancer recurrence in postmenopausal women. However, "too long" becomes a concern when the side effects—such as debilitating joint pain, risk of fractures from osteoporosis, or cardiovascular issues—begin to outweigh the benefits of recurrence prevention. The decision on treatment duration is a highly individualized one, made between a patient and their oncologist, weighing the risks of the disease against the long-term impacts of the medication on quality of life and overall health.
For more information on aromatase inhibitors, you can visit the National Breast Cancer Foundation.
