Background:  Breast cancer is the leading cause of cancer in the United States (1). It is estimated that 84% of breast cancers are hormone positive and may benefit from treatment with estrogen inhibition (2). Aromatase inhibitors (AIs) prevent the production of androgens to estrogen by blocking an enzyme called aromatase. There are three AIs used in the United States: anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). While AIs play a significant role in preventing recurrence and treating metastatic disease (3), many experience aromatase inhibitor associated musculoskeletal symptoms (AIMSS). Incidence of AIMSS may be as high as 50-82% (4). When combined with other recognized adverse effects (cost, pill burden, weight gain, decreased libido, diarrhea, depression), AIMSS may compel many patients to discontinue AI therapy (4-7). While the mechanism of action is not entirely clear, there is emerging evidence that estrogen is chondroprotective; therefore, reducing estrogen levels may lead to AIMSS via cartilage loss and an increase in inflammatory cytokines (7,8). 

Presentation and Diagnosis of AIMSS:  The primary symptoms are arthralgias, joint stiffness, and tendinopathies; AIs are not known to cause neuropathies. Arthralgias may occur anywhere but most commonly occur in the legs, lower back, hands, and wrists (10). Tendinopathies commonly occur in the wrist/hand area and can manifest as de Quervain’s tenosynovitis, trigger fingers, or carpal tunnel syndrome. A possible presenting sign is a wedding ring that no longer fits due to finger swelling. AIMSS symptoms usually start 6-8 weeks after AI initiation and resolve or improve within 2-4 weeks of discontinuation (11). While non-validated criteria for diagnosis are available (12), the presence of stereotypical symptoms within the appropriate time frame should be enough for diagnosis.

Treatment:  Often cancer specialists try to palliate AIMSS, so that patients can continue AI therapy.  Hence, referral to palliative care specialists or pain management specialists may be pursued in the hopes the patient can remain on AI therapy. Appropriate palliative treatment should consider whether AIMSS symptoms are focal or diffuse. 

• Focal symptoms most often occur in the hand or wrist. Conservative management includes NSAIDs, icing, splinting (thumb spica splint for de quervain’s and neutral hand splint for carpal tunnel syndrome), and a course of occupational therapy. Refractory symptoms may respond to corticosteroid injections (13), usually performed by rheumatologists, orthopedic surgeons, physiatrists, or sports medicine physicians. 
• Diffuse symptoms require a systemic approach with a combination of pharmacologic therapy and cardiovascular exercise. 
  • Mild symptoms: consider NSAIDs and/or 2-3 grams per day of acetaminophen (4,14). 
  • Patients with moderate to severe symptoms and/or concomitant depression should be considered for duloxetine (starting at 30 mg daily with titration to 60 mg daily after 1 week) (14). 
  • All patients should participate in a regular exercise program of 30 minutes five days per week of moderate intensity cardiovascular exercise in addition to two days a week of resistance training which has been shown to significantly reduce pain scores (15). 
  • Alternative treatments options to consider include a short course of systemic steroids (e.g. prednisone 5 mg PO for 1 week) or acupuncture (16,17). 
  • Opioids have not been studied for AIMSS but could be considered in refractory cases and/or patients with a limited prognosis. 

When should AI therapy be modified for AIMSS?  Oncologists may consider rotation to a different AI or a different type of endocrine therapy if there is an equally effective systemic cancer treatment that is in line with the patient’s goal of care.  In cases of widespread visceral disease with limited life expectancy, cessation of AI and systemic cancer treatment in general may be warranted. Palliative care and generalist clinicians should involve oncologists in these decisions considering the prognostic complexities involved.

Summary:

• Have a strong index of suspicion for arthralgias/stiffness within 1-2 months of initiating AI therapy
• Consider whether symptoms are focal vs diffuse and if non-pharmacologic management may be better indicated
• Patients with AIMSS and a limited life expectancy from widespread metastases should discuss treatment options with their oncologist including rotation or cessation of treatment.

References

1. “Cancer of the Breast (Female) – Cancer Stat Facts.” SEER, seer.cancer.gov/statfacts/html/breast.html.
2. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf
3. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended therapy in receptor-positive breast cancer. Updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005; 97: 1262-1271.
4. Lombard JM, Zdenkowski N, Wells K, et al. Aromatase inhibitor induced musculoskeletal syndrome: a significant problem with limited treatment options. Support Care Cancer. 2016; 24(5): 2139-2146.
5. Presant, Cary A., et al. “Aromatase Inhibitor–Associated Arthralgia and/or Bone Pain: Frequency and Characterization in Non–Clinical Trial Patients.” Clinical Cancer Updates. 2007; 1(1): 30-33. 
6. Crew KD, Greenlee H, Capodice J, et al. Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early- stage breast cancer. J. Clin Oncol. 2007; 25(25): 3877-3883.
7. Cella, D., Fallowfield, L., Barker, P., Cuzick, J., Locker, G., & Howell, A. (2006). Quality of Life of Postmenopausal Women in the ATAC (“Arimidex”, Tamoxifen, Alone or in Combination) Trial after Completion of 5 years’ Adjuvant Treatment for Early Breast Cancer. Breast Cancer Research and Treatment, 100(3), 273-284.
8. Zhang Y, McAlindon TE, Hannan MT, et al. Estrogen replacement therapy and worsening of radiographic knee OA: the Framingham Study. Arthritis Rheum. 1998; 41: 1867-1873. 
9. Gallicchio L, MacDonald R, Helzlsouer KJ. Insulin-like growth factor 1 and musculoskeletal pain among breast cancer patients on aromatase inhibitor therapy and women without a history of cancer. J Cancer Res Clin Oncol. 2013; 139(5): 837-843. 
10. Mao JJ, Stricker C, Bruner D, et al. Patterns and risk factors associated with aromatase inhibitor related arthralgia among breast cancer survivors. Cancer. 2009; 115: 3631-3639.
11. Lintermans A, Laenen A, Van Calster B, et al. Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data. Annals of Oncology, vol. 24, no. 2, 2013, pp. 350–355.
12. Wisotzky, Eric M, and Katherine Power. “Chapter 77 Aromatase Inhibitor-Induced Musculoskeletal Symptoms.” Cancer Rehabilitation, 2nd ed., Springer Publishing Company, 2019, pp. 972–978
13. Mardani-Kivi M, Mobarakeh MK, Bahrami F, et al. Corticosteroid injection with or without thumb spica cast for de Quervain tenosynovitis. J Hand Surg Am. 2014;39(1):37–41.
14. Henry, N. Lynn, et al. “Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor–Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202.” Journal of Clinical Oncology, vol. 36, no. 4, Jan. 2018, pp. 326–332.
15. Irwin ML, Cartmel B, Gross CP, et al. Randomized exercise trial of aromatase inhibitor–induced arthralgia in breast cancer survivors. J Clin Oncol. 2015;33(10):1104–1111.
16. Kubo M, Onishi H, Kuroki S, et al. Short-term and low-dose prednisolone administration reduces aromatase inhibitor-induced arthralgia in patients with breast cancer. Anticancer Res. 2012;32(6):2331–2336.
17. Hershman, Dawn L., et al. “Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer.” Jama. 2018; 320(2): 167.

Version History: First electronically published in July 2020; originally edited by Sean Marks MD

Author Affiliation: University of Michigan, Ann Arbor, MI

Conflicts of Interest: Nothing to disclose