Aromatase Inhibitor-induced Arthralgia

Abstract & Commentary

By Gary. R. Shapiro, MD

Medical Director, Cancer Center of Western Wisconsin, New Richmond, Wisconsin

Dr. Shapiro reports no financial relationships relevant to this field of study.

Synopsis: Aromatase inhibitor-induced arthralgia develops by week 6 of initiating aromatase inhibitor (AI) therapy, and does not appear to resolve. In fact, it usually worsens over the first year of AI therapy. Women who have severe menopausal symptoms or existing joint-related conditions at the time they start taking AIs had worse arthralgia.

Source:Castel LD, et al. Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort. Cancer 2013;119:2375-2382.

This prospective cohort study measured joint pain in 91 women beginning adjuvant aromatase inhibitor (AI) therapy for postmenopausal breast cancer. These women were asked to rate pain in eight joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes) at baseline and 2, 4, 6, 8, 12, and 52 weeks after they started taking the AI. A comparison group of 177 postmenopausal women without breast cancer completed the same surveys, using the same time frame, to assess the background rate of arthralgia in menopause.

At baseline, the AI and comparison groups did not differ in their composite arthralgia score, but, by week 6, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means, 1.8; 95% confidence interval, 1.24-2.7; P = 0.002). Arthralgia did not appear to resolve with time, but continued to worsen in the AI group over the entire 1-year period of the study.

Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe arthralgia over time. Additional clinical, demographic, and health-related quality of life variables were assessed, but none of these appear to be risk factors for aromatase inhibitor-induced arthralgia (AIA).

With regard to adherence, over the 1-year course of the study, 83% of the women initiating AI were reported as still taking either the AI they initiated or another AI; 12% were reported switched to tamoxifen; and 5% were reported as having discontinued adjuvant endocrine therapy entirely.

COMMENTARY

Despite the fact that AIs improve breast cancer disease-free survival in postmenopausal women with early-stage, hormone-receptor-positive breast cancer, only 50-70% of women are adherent to their AI medication at 3 years,1 well short of the 5-year course of therapy that is the standard of care. Although the reasons for nonadherence are not clear, AIA is common, and, in conjunction with the vasomotor and bone-health side effects, likely plays a significant role in explaining this significant dropout rate. Even for those who remain compliant with the prescribed course of therapy, the negative impact of AIs on their quality of life may be profound.

The prevalence of AIA is said to range between 5% and 35%. AIA usually presents with symmetrical joint pains, most commonly affecting the wrists, hands, and knees. Complaints of carpal tunnel syndrome and trigger finger symptoms are not uncommon, as are morning stiffness, myalgia, and decreased grip strength.1

Although nearly all oncologists appreciate the significance of AIA, the paucity of prospective studies designed specifically to elucidate this problem has left clinicians without a clear understanding of the risk factors for AIA and its natural history. The Castel study was intentionally designed to longitudinally assess arthralgia, clinical and patient-reported arthralgia predictors, and other clinical and patient-reported outcomes. Accordingly, its findings have practical implications for clinicians.

It is no surprise to learn that women taking AIs have more severe arthralgia than women in the postmenopausal comparison group. That these symptoms continue to worsen with time and do not appear to resolve over the first year is, however, useful new information that was not made clear by previous studies that had less rigorous design and outcome measurements. It suggests that women should return for their initial follow-up 6 weeks after initiating AI therapy, the time that it usually takes for AIA to develop, and that they should be monitored for worsening symptoms throughout the entire first year of AI therapy.

By the end of her study, Castel found that 27% of women had stopped taking an AI and 5% had discontinued adjuvant hormonal therapy altogether (12% switched to tamoxifen after experiencing unacceptable AI-related side effects). Although this number is below the 30-50% 3-year dropout rate reported in other studies, it suggests that AIA and other side effects continue to worsen with the passage of time. If women are to realize the maximum effect of these agents, physicians will need to monitor and treat these symptoms throughout the course of therapy. AIs may continue to adversely impact the health and quality of life of a breast cancer patient for years after she has completed therapy, and "survivorship plans" should be constructed accordingly. Future research should extend the observation period beyond the 1-year studied by Castel and should add a therapeutic focus.

Although AIA is a common problem, there have been surprisingly few prospective, randomized, controlled studies to explore management strategies. Most treatments, including NSAIDs, have been based on extrapolations from the management of osteoarthritis and rheumatoid arthritis. These include counseling and education, lifestyle modifications like exercise and weight loss, massage, relaxation techniques, and hypnosis. Calcium and vitamin D, opioid and non-opioid analgesics, and other pain modifiers, like tricyclic antidepressants or anticonvulsants, are among the various pharmacologic interventions that have been used.

One of the few prospective, randomized, controlled clinical trials explored the role of acupuncture in managing AIA, and found that women who received true acupuncture twice weekly for 6 weeks had less pain and pain-related symptoms than those who received sham acupuncture. Although this study was small (43 women) it raises interesting possibilities for treating AIA and for future research.2

The ATOLL study showed that women who do not tolerate one AI because of AIA might be able to tolerate an alternative AI. In this study, women who stopped taking anastrozole because of AIA were switched to letrozole and reported less pain and better quality of life. However, it is important to note that these women were observed for only 6 months, and though the letrozole was better tolerated, 74% of the women still had significant arthralgia after 6 months of letrozole therapy.3 It is essential that the strategy of "switching AIs" be studied over a longer period of time in light of what Castel has demonstrated about the natural history of AIA.

Another "switching strategy" is to prescribe tamoxifen in women who have unacceptable AIA. Although tamoxifen is associated with a lower incidence of AIA, tamoxifen does have a significantly higher risk for deep venous thrombosis, pulmonary embolism, and stroke when compared with AI. This risk may not be insignificant in the older postmenopausal woman who frequently suffers from comorbidities that increase her risk for these tamoxifen-related thromboembolic side effects.

Finally, it is important to highlight Castel’s finding that women taking AIs with more severe menopausal symptoms or existing joint-related conditions at the time of AI initiation had worse arthralgia over time. Targeted interventions in these at-risk groups may improve AI compliance and improve quality of life. Knowing who may be at risk for AIA, oncologists are better able to help their patients make informed decisions about the benefits and burdens of AI therapy and compare these to alternative adjuvant approaches.

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Briot K, et al. Breast Cancer Res Treat 2010;120:127-134.