Arthralgias and Aromatase Inhibition
Arthralgias and Aromatase Inhibition
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a cross-sectional analysis of 300 postmenopausal breast cancer patients treated with aromatase inhibitors, the occurrence of treatment-related arthralgia (by self-report) was approximately 50%. The symptoms were more frequent in women who were closer to the menopause transition and generally occurred within three months after treatment initiation.
Source: Mao JJ, et al. Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer. 2009;115:3631-3639.
Aromatase inhibitors (AI), such as anastrozole, letrozole, and exemestane are widely prescribed for the treatment of postmenopausal breast cancer, as large, randomized, controlled trials have produced improvements in disease-free survival rates as high as 40% in the adjuvant setting.1-3 AI-related arthralgia has become increasingly recognized as a symptom complex that both impedes quality of life and reduces compliance among treated patients.4-6 The aims of the current investigation were to further characterize AI-associated arthralgia in terms of rate, severity, and risk factors.
To this end, a cross-sectional survey of postmenopausal breast cancer patients, who were receiving adjuvant AI therapy at a university-based oncology clinic, was undertaken. Enrolled patients were asked to complete a questionnaire regarding joint pain and medication. Multivariate logistic regression analyses were performed to evaluate risk factors.
Among 300 survey respondents, 139 (47%) attributed AI as a cause of their current arthralgia. Of those patients, 74% recognized the onset of AI-associated joint pain within three months of starting medication and 67% rated joint pain as moderate or severe in the previous seven days. In bivariate analysis, younger age, time since last menstrual period (LMP), prior chemotherapy that included a taxane, and a weight gain of 10 or more pounds were each associated with AI arthralgia. However, in multivariate logistic regression analyses, the time since LMP was the only significant predictor. Controlling for covariates, women who had their LMP within five years had the highest probability of reporting AI arthralgia (73%), whereas those who had their LMP > 10 years previously had the lowest probability of reporting AI arthralgia (35%; adjusted odds radio, 3.39; 95% confidence interval, 1.21-9.44; p = .02). Wrists/ hands, ankles/feet, elbows, and knees appeared to be associated more strongly with AI treatment (all p < .01). Symptoms began within the first three months of therapy in most patients.
Commentary
This cross-sectional survey found the prevalence of AI arthralgia to be quite high, to prominently involve distal joints (wrist, hands, feet, ankles, knees), to occur within months after initiating treatment, and to be most evident in women who recently transitioned through menopause compared to older women. Although relying on self-report, the methodology was sound and the high rate of survey completion (95%) was excellent. The population of breast cancer patients might be somewhat younger than that encountered in community practice and, that fact alone, might account for the high rate (nearly 50%) of AI arthralgia observed.
The fact that AI arthralgia was more common in younger women suggests that estrogen withdrawal may play a role in the mechanism of this disorder; a concept that has been forwarded previously.4,5,7 Women who have just transitioned through menopause may have higher residual circulating estrogen, and the exposure to aromatase inhibitors may result in a more dramatic change in hormonal milieu. It is known that estrogen levels influence endogenous opioid generation,8 and the authors have speculated that a rapid reduction might reduce pain threshold. Estrogens also downregulate proinflammatory cytokines,9 and it is also conceivable that the more pronounced effects of aromatase inhibition in younger women also lead to accelerated bone and joint inflammatory processes and increased pain.10
To the extent that arthralgias influence quality of life and adherence to prescribed AI treatment, additional research is needed to clarify pathogenesis and to establish effective treatment strategies. It is quite possible that the intended therapeutic effect (reduction in estrogen) is also the cause. In that case, physical therapy, analgesics, and/or anti-inflammatory medicine may prove optimal management.
References
1. Goss PE, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-1802.
2. Howell A, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005;365:60-62.
3. Jakesz R, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005;366:455-462.
4. Burstein HJ, Winer EP. Aromatase inhibitors and arthralgias: a new frontier in symptom management for breast cancer survivors. J Clin Oncol. 2007;25: 3797-3799.
5. Coleman RE, et al. Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev. 2008;34:275-282.
6. Donnellan PP, et al. Aromatase inhibitors and arthralgia. J Clin Oncol. 2001;19:2767.
7. Josse RG. Roles for estrogen in bone loss and arthralgia during aromatase inhibitor treatment. Curr Opin Oncol. 2007;19:S1-S8.
8. Craft RM. Modulation of pain by estrogens. Pain. 2007;132 Suppl 1:S3-12.
9. Sun WH, et al. Estrogen inhibits phorbol ester-induced I[kappa]B[alpha] transcription and protein degradation. Biochemical and Biophysical Research Communications. 1998;244:691-695.
10. Carlsten H. Immune responses and bone loss: the estrogen connection. Immunol Rev. 2005;208:194-206.
In a cross-sectional analysis of 300 postmenopausal breast cancer patients treated with aromatase inhibitors, the occurrence of treatment-related arthralgia (by self-report) was approximately 50%. The symptoms were more frequent in women who were closer to the menopause transition and generally occurred within three months after treatment initiation.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.