Breast Cancer Research and Treatment

, Volume 120, Issue 3, pp 525–538 | Cite as

Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more?

  • Omar S. Din
  • David Dodwell
  • Richard J. Wakefield
  • Robert E. Coleman
Review

Abstract

Aromatase inhibitors (AIs) are a standard of care for the adjuvant treatment of hormone responsive early carcinoma of the breast as demonstrated in a number of large international phase III randomised trials. Arthralgia was a somewhat unexpected side effect of this class of agents and has proven to be potentially problematic in clinical practice. Although rates of up 35% have been reported in the randomised trials, the figure has been much higher in subsequent case series. There is concern that these symptoms are significant and may affect compliance and thus the overall efficacy of treatment. It is therefore extremely important that we evaluate this syndrome with a view to gaining more information regarding its clinical features and possible aetiological mechanism. The potential aetiological mechanisms and evidence for aromatase inhibitor-induced arthralgia (AIA) are reviewed in this article. Looking forward, it is now important that prospective clinical trials are well designed to evaluate this syndrome and potential therapeutic strategies to circumvent it. Radiological imaging and biochemical analyses may help our understanding of AIA and these are discussed.

Keywords

Aromatase inhibitors Arthralgia Imaging Review Breast cancer 

References

  1. 1.
    EBCTCG (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717CrossRefGoogle Scholar
  2. 2.
    Bonneterre J et al (2000) Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18(22):3748–3757PubMedGoogle Scholar
  3. 3.
    Mouridsen H et al (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21(11):2101–2109CrossRefPubMedGoogle Scholar
  4. 4.
    Nabholtz JM et al (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18(22):3758–3767PubMedGoogle Scholar
  5. 5.
    Howell A et al (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365(9453):60–62CrossRefPubMedGoogle Scholar
  6. 6.
    Goss PE et al (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349(19):1793–1802CrossRefPubMedGoogle Scholar
  7. 7.
    Coombes RC et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092CrossRefPubMedGoogle Scholar
  8. 8.
    Coombes RC et al (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369(9561):559–570CrossRefPubMedGoogle Scholar
  9. 9.
    Jakesz R et al (2005) 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 366(9484):455–462CrossRefPubMedGoogle Scholar
  10. 10.
    Thurlimann B et al (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757CrossRefPubMedGoogle Scholar
  11. 11.
    Boccardo F et al (2006) Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 17(7): vii10–4Google Scholar
  12. 12.
    Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354(3):270–282CrossRefPubMedGoogle Scholar
  13. 13.
    Njar VC, Brodie AM (1999) Comprehensive pharmacology and clinical efficacy of aromatase inhibitors. Drugs 58(2):233–255CrossRefPubMedGoogle Scholar
  14. 14.
    Campos SM (2004) Aromatase inhibitors for breast cancer in postmenopausal women. Oncologist 9(2):126–136CrossRefPubMedGoogle Scholar
  15. 15.
    di Salle E et al (1992) Exemestane (FCE 24304), a new steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 43(1–3):137–143PubMedGoogle Scholar
  16. 16.
    Greendale GA, Lee NP, Arriola ER (1999) The menopause. Lancet 353(9152):571–580CrossRefPubMedGoogle Scholar
  17. 17.
    Cecil RL, Archer BH (1925) Arthritis of the menopause. JAMA 84:75–79Google Scholar
  18. 18.
    Avis N et al (2004) Baillere’s clinical endocrinology and metabolism. In: Burger H (ed) The evolution of menopausal symptoms. Bailliere Tindall, LondonGoogle Scholar
  19. 19.
    Dugan SA et al (2006) Musculoskeletal pain and menopausal status. Clin J Pain 22(4):325–331CrossRefPubMedGoogle Scholar
  20. 20.
    Xu J et al (2005) Natural history of menopause symptoms in primary care patients: a MetroNet study. J Am Board Fam Pract 18(5):374–382CrossRefPubMedGoogle Scholar
  21. 21.
    Szoeke CE et al (2008) The relationship of reports of aches and joint pains to the menopausal transition: a longitudinal study. Climacteric 11(1):55–62CrossRefPubMedGoogle Scholar
  22. 22.
    Huang C et al (1997) Factors associated with joint pain among postmenopausal women. Int J Obes Relat Metab Disord 21(5):349–354CrossRefPubMedGoogle Scholar
  23. 23.
    Dowsett M, Lonning PE (1997) Anastrozole–a new generation in aromatase inhibition: clinical pharmacology. Oncology 54(Suppl 2):11–14CrossRefPubMedGoogle Scholar
  24. 24.
    Nielsen RH et al (2008) Oestrogen exhibits type II collagen protective effects and attenuates collagen-induced arthritis in rats. Clin Exp Immunol 152(1):21–27PubMedCrossRefGoogle Scholar
  25. 25.
    Cvoro A et al (2008) Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol 180(1):630–636PubMedGoogle Scholar
  26. 26.
    Dawson-Basoa M, Gintzler AR (1997) Involvement of spinal cord delta opiate receptors in the antinociception of gestation and its hormonal simulation. Brain Res 757(1):37–42CrossRefPubMedGoogle Scholar
  27. 27.
    Riley JL 3rd et al (1999) A meta-analytic review of pain perception across the menstrual cycle. Pain 81(3):225–235CrossRefPubMedGoogle Scholar
  28. 28.
    Dietrich W et al (2006) Estrogen receptor-beta is the predominant estrogen receptor subtype in normal human synovia. J Soc Gynecol Investig 13(7):512–517PubMedGoogle Scholar
  29. 29.
    Coleman RE et al (2008) Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 34(3):275–282CrossRefPubMedGoogle Scholar
  30. 30.
    Richette P, Corvol M, Bardin T (2003) Estrogens, cartilage, and osteoarthritis. Joint Bone Spine 70(4):257–262CrossRefPubMedGoogle Scholar
  31. 31.
    Sniekers YH et al (2008) Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment—a systematic approach. Osteoarthr Cartil 16(5):533–541CrossRefPubMedGoogle Scholar
  32. 32.
    Oestergaard S et al (2006) Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation. Arthritis Rheum 54(8):2441–2451CrossRefPubMedGoogle Scholar
  33. 33.
    Nevitt MC et al (2001) The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: The Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 44(4):811–818CrossRefPubMedGoogle Scholar
  34. 34.
    Le Bail J et al (2001) Aromatase in synovial cells from postmenopausal women. Steroids 66(10):749–757CrossRefPubMedGoogle Scholar
  35. 35.
    Sasano H et al (1997) Aromatase in human bone tissue. J Bone Miner Res 12(9):1416–1423CrossRefPubMedGoogle Scholar
  36. 36.
    Toesca A et al (2008) Estrogen and progesterone receptors in carpal tunnel syndrome. Cell Biol Int 32(1):75–79CrossRefPubMedGoogle Scholar
  37. 37.
    Morel B, Marotte H, Miossec P (2007) Will steroidal aromatase inhibitors induce rheumatoid arthritis? Ann Rheum Dis 66(4):557–558CrossRefPubMedGoogle Scholar
  38. 38.
    Laroche M et al (2007) Joint pain with aromatase inhibitors: abnormal frequency of Sjogren’s syndrome. J Rheumatol 34(11):2259–2263PubMedGoogle Scholar
  39. 39.
    Henry NL et al (2008) Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat 111(2):365–372CrossRefPubMedGoogle Scholar
  40. 40.
    Pfeilschifter J et al (2002) Changes in proinflammatory cytokine activity after menopause. Endocr Rev 23(1):90–119CrossRefPubMedGoogle Scholar
  41. 41.
    Mao JJ et al (2009) Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer 115(16):3631–3639CrossRefPubMedGoogle Scholar
  42. 42.
    Sestak I et al (2008) Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol 9(9):866–872CrossRefPubMedGoogle Scholar
  43. 43.
    Buzdar A (2006) Clinical features of joint symptoms observed in the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial. J Clin Oncol 24(18S): 551Google Scholar
  44. 44.
    Buzdar A et al (2006) Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 7(8):633–643CrossRefPubMedGoogle Scholar
  45. 45.
    Fallowfield L et al (2004) Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial. J Clin Oncol 22(21):4261–4271CrossRefPubMedGoogle Scholar
  46. 46.
    Cella D et al (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 Res Treat 100(3):273–284CrossRefPubMedGoogle Scholar
  47. 47.
    Khanduri S, Dodwell DJ (2007) Aromatase inhibitors and musculoskeletal symptoms. Breast 17(1):76–79CrossRefPubMedGoogle Scholar
  48. 48.
    Cuzick J et al (2008) Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol 9(12):1143–1148CrossRefPubMedGoogle Scholar
  49. 49.
    Fallowfield L (2008) There’s many a slip twixt cup and lip: adherence issues in cancer therapy. Nat Clin Pract Oncol 5(3):118–119CrossRefPubMedGoogle Scholar
  50. 50.
    Chlebowski RT, Geller ML (2006) Adherence to endocrine therapy for breast cancer. Oncology 71(1–2):1–9PubMedGoogle Scholar
  51. 51.
    Fallowfield LJ et al (2006) Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 24(6):910–917CrossRefPubMedGoogle Scholar
  52. 52.
    Whelan TJ et al (2005) Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23(28):6931–6940CrossRefPubMedGoogle Scholar
  53. 53.
    Felson DT (2008) Comparing the prevalence of rheumatic diseases in China with the rest of the world. Arthritis Res Ther 10(1):106CrossRefPubMedGoogle Scholar
  54. 54.
    Crew KD et al (2007) Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25(25):3877–3883CrossRefPubMedGoogle Scholar
  55. 55.
    Presant CA et al (2007) Aromatase inhibitor-associated arthralgia and/or bone pain: frequency and characterization in non-clinical trial patients. Clin Breast Cancer 7(10):775–778CrossRefPubMedGoogle Scholar
  56. 56.
    Dent SF et al (2007) Adjuvant aromatse inhibitors in early breast cancer—toxicity and adherence. Important observations in clinical practice. In: San Antonio breast cancer symposium. San Antonio, TexasGoogle Scholar
  57. 57.
    Renshaw L et al (2007) Comparison of joint problems as reported by patients in a randomised adjuvant trial of anastrozole and letrozole. In: San Antonio breast caner symposium, p 2072Google Scholar
  58. 58.
    Morales L et al (2007) Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat 104(1):87–91CrossRefPubMedGoogle Scholar
  59. 59.
    Morales L et al (2008) Prospective study to assess short-term intra-articular and tenosynovial changes in the aromatase inhibitor-associated arthralgia syndrome. J Clin Oncol 26(19):3147–3152CrossRefPubMedGoogle Scholar
  60. 60.
    Alegre-Sancho JJ et al (2008) Trigger thumb in patients with breast cancer and hand pain associated with aromatase inhibitors. Ann Rheum Dis 67(Suppl II)Google Scholar
  61. 61.
    Dizdar O et al (2009) Sonographic and electrodiagnostic evaluations in patients with aromatase inhibitor-related arthralgia. J Clin Oncol 27(30):4955–4960CrossRefPubMedGoogle Scholar
  62. 62.
    Sestak I, Sapunar F, Cuzick J (2009) Aromatase inhibitor-induced carpal tunnel syndrome: results from the ATAC trial. J Clin Oncol 27(30):4961–4965CrossRefPubMedGoogle Scholar
  63. 63.
    Sestak I, Cuzick J (2007) Risk factors for joint symptoms in the ATAC trial. In: San Antonio breast caner symposium, p 2071Google Scholar
  64. 64.
    Singh S, Howell A, Cuzick J (2006) Vit D levels among patients with arthralgia: results from IBIS-II breast cancer prevention study. In: San Antonio breast caner symposium, p 1068Google Scholar
  65. 65.
    Azria D et al (2007) Letrozole induced arthralgia: results of a multicentric prospective trial exploring clinical parameters and plasma biomarkers. In: ASCO breast cancer symposium, p 228Google Scholar
  66. 66.
    Khan QJ et al (2010) Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 119(1):111–118CrossRefPubMedGoogle Scholar
  67. 67.
    Mao JJ et al (2009) Feasibility trial of electroacupuncture for aromatase inhibitor-related arthralgia in breast cancer survivors. Integr Cancer Ther 8(2):123–129CrossRefPubMedGoogle Scholar
  68. 68.
    Crew KD et al (2009) Randomized, blinded, placebo-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol 27(15s): 571Google Scholar
  69. 69.
    Basch E et al (2006) Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol 7(11):903–909CrossRefPubMedGoogle Scholar
  70. 70.
    Hershman DL (2008) Getting a grip on aromatase inhibitor-associated arthralgias. J Clin Oncol 26(19):3120–3121CrossRefPubMedGoogle Scholar
  71. 71.
    Allen KD et al (2007) Validity and factor structure of the AUSCAN Osteoarthritis Hand Index in a community-based sample. Osteoarthr Cartil 15(7):830–836CrossRefPubMedGoogle Scholar
  72. 72.
    Sautner J et al (2004) Development of the M-SACRAH, a modified, shortened version of SACRAH (Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands). Rheumatology 43(11):1409–1413CrossRefPubMedGoogle Scholar
  73. 73.
    Sautner J et al (2009) A comparison of the Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands and the Australian/Canadian Osteoarthritis Hand Index in Hand Osteoarthritis Patients. Int J Rheumatol 1–7Google Scholar
  74. 74.
    Harkonen R, Harju R, Alaranta H (1993) Accuracy of the Jamar dynamometer. J Hand Ther 6(4):259–262PubMedGoogle Scholar
  75. 75.
    Mathiowetz V et al (1984) Reliability and validity of grip and pinch strength evaluations. J Hand Surg Am 9(2):222–226PubMedGoogle Scholar
  76. 76.
    Backhaus M et al (2001) Guidelines for musculoskeletal ultrasound in rheumatology. Ann Rheum Dis 60(7):641–649CrossRefPubMedGoogle Scholar
  77. 77.
    Wakefield RJ et al (2005) Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 32(12):2485–2487PubMedGoogle Scholar
  78. 78.
    Schmidt WA (2007) Technology insight: the role of color and power Doppler ultrasonography in rheumatology. Nat Clin Pract Rheumatol. 3(1): 35–42 (quiz 59)Google Scholar
  79. 79.
    Tan AL, Emery P (2008) Role of oestrogen in the development of joint symptoms? Lancet Oncol 9(9):817–818CrossRefPubMedGoogle Scholar
  80. 80.
    Tan AL et al (2003) Imaging of the musculoskeletal system: magnetic resonance imaging, ultrasonography and computed tomography. Best Pract Res Clin Rheumatol 17(3):513–528CrossRefPubMedGoogle Scholar
  81. 81.
    Haavardsholm EA et al (2007) Introduction of a novel magnetic resonance imaging tenosynovitis score for rheumatoid arthritis: reliability in a multireader longitudinal study. Ann Rheum Dis 66(9):1216–1220CrossRefPubMedGoogle Scholar
  82. 82.
    Haavardsholm EA et al (2005) Reliability and sensitivity to change of the OMERACT rheumatoid arthritis magnetic resonance imaging score in a multireader, longitudinal setting. Arthritis Rheum 52(12):3860–3867CrossRefPubMedGoogle Scholar
  83. 83.
    Lester JE et al (2008) Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer. Clin Cancer Res 14(19):6336–6342CrossRefPubMedGoogle Scholar
  84. 84.
    Brufsky A et al (2008) Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 13(5):503–514CrossRefPubMedGoogle Scholar
  85. 85.
    Ellis GK et al (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 26(30):4875–4882CrossRefPubMedGoogle Scholar
  86. 86.
    Haugeberg G et al (2006) Hand bone loss in early undifferentiated arthritis: evaluating bone mineral density loss before the development of rheumatoid arthritis. Ann Rheum Dis 65(6):736–740CrossRefPubMedGoogle Scholar
  87. 87.
    Haugeberg G et al (2007) Hand bone densitometry: a more sensitive standard for the assessment of early bone damage in rheumatoid arthritis. Ann Rheum Dis 66(11):1513–1517CrossRefPubMedGoogle Scholar
  88. 88.
    Henry NL et al (2008) A distinct inflammatory marker pattern in patients with aromatase inhibitor (AI)-induced musculoskeletal symptoms. In: SABCS. San Antonio, TexasGoogle Scholar
  89. 89.
    Hunter DJ et al (2007) Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study. Arthritis Res Ther 9(5):R108CrossRefPubMedGoogle Scholar
  90. 90.
    Williams FM, Spector TD (2008) Biomarkers in osteoarthritis. Arthritis Res Ther 10(1):101CrossRefPubMedGoogle Scholar
  91. 91.
    Landewe R (2007) Predictive markers in rapidly progressing rheumatoid arthritis. J Rheumatol Suppl 80:8–15PubMedGoogle Scholar
  92. 92.
    Wild N et al (2008) Diagnosis of rheumatoid arthritis: multivariate analysis of biomarkers. Biomarkers 13(1):88–105CrossRefPubMedGoogle Scholar
  93. 93.
    ClinicalTrials.gov. 2009 7th July 2009]; Available from: http://clinicaltrials.gov/ct2/results?term=breast+cancer+AND+arthralgia
  94. 94.
    Jakesz R et al (2007) Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst 99(24):1845–1853CrossRefPubMedGoogle Scholar
  95. 95.
    Burstein HJ (2007) Aromatase inhibitor-associated arthralgia syndrome. Breast 16(3):223–234CrossRefPubMedGoogle Scholar
  96. 96.
    Bianchi S et al. (2007) Ultrasound of the digital flexor system: normal and pathological findings. J Ultrasound 10:85–92CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Omar S. Din
    • 1
  • David Dodwell
    • 2
  • Richard J. Wakefield
    • 3
  • Robert E. Coleman
    • 1
  1. 1.Academic Unit of Clinical OncologyCancer Research Centre, Weston Park HospitalSheffieldUK
  2. 2.Department of Clinical Oncology, Leeds Institute of Oncology, Bexley WingSt James’ University HospitalLeedsUK
  3. 3.Academic Unit of Musculoskeletal Disease, Leeds Institute of Molecular MedicineChapel Allerton HospitalLeedsUK

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