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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3877-3883 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7573 Prevalence of Joint Symptoms in Postmenopausal Women Taking Aromatase Inhibitors for Early-Stage Breast Cancer
From the Department of Medicine and the Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons; and the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY Address reprint requests to Dawn L. Hershman, MD, MS, Columbia University, 161 Fort Washington Ave, 10-1068, New York, NY 10032; e-mail: dlh23{at}columbia.edu
Purpose: Aromatase inhibitors (AIs) improve survival in postmenopausal women with hormone-sensitive breast cancer, but can cause joint pain and stiffness. The purpose of the current study was to evaluate the prevalence of and identify risk factors for AI-related joint symptoms. Patients and Methods: We performed a cross-sectional survey of consecutive postmenopausal women receiving adjuvant AI therapy for early-stage hormone-sensitive breast cancer at an urban academic breast oncology clinic. Patients completed a 25-item self-administered questionnaire assessing the presence of joint symptoms that started or worsened after initiating AIs. Multivariate regression was used to compare those with AI-related arthralgia with those who did not report symptoms, adjusting for demographic and clinical factors. Results: Of 200 patients who completed the survey, 94 (47%) reported having AI-related joint pain and 88 (44%) reported AI-related joint stiffness. In multiple logistic regression analysis, being overweight (body mass index of 25 to 30 kg/m2) and prior tamoxifen therapy were inversely associated with AI-related joint symptoms. Patients who received taxane chemotherapy were more than four times more likely than other patients to have AI-related joint pain and stiffness (odds ratio [OR] = 4.08, 95% CI, 1.58 to 10.57 and OR = 4.76; 95% CI, 1.84 to 12.28, respectively). Conclusion: Our study suggests that AI-related joint symptoms are more prevalent than what has been described previously in clinical trials. The success of AI therapy depends on patients' ability to adhere to treatment recommendations; therefore, additional studies of interventions that may alleviate these symptoms are needed.
Because of early detection and improved treatments, women with breast cancer are living longer.1 The increase in breast cancer survival is largely due to the benefits of hormonal therapy, such as tamoxifen and aromatase inhibitors (AIs), for the treatment of hormone-sensitive breast cancer. Recent clinical trials have demonstrated that AIs are more effective than tamoxifen at reducing breast cancer recurrences.2-8 However, breast cancer patients receiving AIs have a higher incidence of osteoporosis, bone fractures, and musculoskeletal symptoms, particularly joint pain and stiffness. Among women enrolled onto a randomized trial in the adjuvant setting (Arimidex, Tamoxifen, Alone or in Combination trial), the incidence of musculoskeletal disorders was 27.8% in patients taking anastrozole versus 21.3% in patients taking tamoxifen.2 However, these symptoms were assessed broadly using the National Cancer Institute Common Terminology Criteria,9 which may result in a misrepresentation of the true prevalence and severity of this adverse effect. Studies have shown inconsistencies between patient versus clinician reporting of toxic effects,10 as well as differences in the reporting of adverse events in the National Cancer Institute clinical database compared with trial publications.11 AIs suppress plasma estrogen levels in postmenopausal women by inhibiting the enzyme responsible for the conversion of androgens to estrogens in peripheral tissues (skin, muscle, fat, and benign and malignant breast tissue).12,13 Estrogen deficiency after menopause has been linked to an increase in several chronic inflammatory conditions, including osteoporosis and osteoarthritis (OA), and although the exact mechanism of AI-related arthralgia is unclear, it is believed to be related to estrogen deprivation.14,15 The current study was initiated to evaluate the prevalence and severity of joint symptoms related to AI use in the community, and to define factors that may be associated with an increased risk of this treatment-related adverse effect.
Sample We conducted a cross-sectional survey at the Breast Oncology Clinic of Columbia University Medical Center (New York, NY). Potential participants included all postmenopausal women with a history of stage I to III hormone receptor–positive breast cancer who were currently taking a third-generation AI (anastrozole, letrozole, or exemestane) for at least 3 months and were seen between May and September 2006. Additional inclusion criteria were histologically confirmed estrogen receptor–positive and/or progesterone receptor–positive primary breast cancer, approval of the patient's primary treating oncologist, and the patient's ability to understand and provide written informed consent in English or Spanish. Institutional Review Board approval was obtained before commencement of the study. Using a cross-sectional design, potential participants were screened and identified during routine follow-up visits. Of 253 consecutive patients screened, six (2%) declined enrollment, 22 (9%) were ineligible due to discontinuation of AI therapy or presence of metastatic disease, and 25 (10%) did not show up for their scheduled appointment, leaving a total of 200 participants. After informed consent was obtained, each participant was given a self-administered 25-item survey in either English or Spanish. The participants were unaware of the study hypothesis, but were told that the survey was being conducted to assess for potential adverse effects related to their cancer treatments.
Outcome Assessment The main outcomes were patient report of any joint pain or stiffness in the last week that had either started or worsened after initiating AI therapy, severity of joint pain or stiffness on a 0 to 10 scale, location of affected joints, use of oral medications or supplements to relieve joint symptoms, degree of pain relief from these oral medications on a 0 to 10 scale, and use of nonpharmacologic interventions to relieve joint symptoms. The questions on pain or stiffness severity and degree of pain/stiffness relief were adapted from the Brief Pain Inventory Short Form.16 Assessment of location of affected joints was adapted from standard geriatric pain assessment scales. On the 11-point scale, patients were classified as having mild symptoms if they reported a score of 1 to 4, moderate symptoms if they reported a score of 5 to 7, and severe symptoms if the score was 8 or more. To determine the presence of AI-related arthralgia, women were asked, "Have you had any joint pain/stiffness in the past week?" and then subsequently asked, "Did this joint pain/stiffness get worse after initiating therapy with an aromatase inhibitor?" and "Did you have joint pain/stiffness which started after initiating therapy with an aromatase inhibitor?"
Statistical Analysis
Baseline Descriptive Statistics Between May and September 2006, 200 patients were enrolled. Baseline demographic characteristics are described in Table 1. The median age of the women enrolled was 63 years (range, 35 to 90 years). One hundred twenty patients (60%) were non-Hispanic white, 54 patients (27%) were Hispanic, 19 patients (10%) were non-Hispanic black, and six patients (3%) were Asian.
The median time since menopause was 12 years (range, 1 to 52 years). One hundred twenty-three patients (64%) experienced natural menopause, 30 (16%) underwent surgical menopause, and 38 patients (20%) reported chemically induced menopause (Table 2). One hundred twenty-eight patients (64%) took anastrozole, 38 patients (19%) took letrozole, and 33 patients (17%) took exemestane. The median duration on AI therapy was 18 months (range, 3 to 66 months).
Of the total sample, 94 patients (47%) reported having AI-related joint pain: 47 (23.5%) had new-onset joint pain, and 47 patients (23.5%) had worsening of prior joint pain after starting adjuvant AI therapy. Eighty-eight patients (44%) reported AI-related joint stiffness: 53 patients (26.5%) had new-onset joint stiffness and 35 patients (17.5%) had exacerbation of baseline joint stiffness with AI therapy. Of those who reported AI-related joint pain (n = 94), 63 patients (67%) experienced moderate to severe symptoms (Fig 1). Similarly, among women with AI-related joint stiffness (n = 88), 58 patients (66%) reported moderate to severe symptoms. The most common joints affected by AI-related arthralgia included the hands, knees, and back (Fig 1).
Predictors of AI-Related Arthralgia In a univariate analysis (Table 2), presence of AI-related joint symptoms was not associated with age, race, entry into menopause (natural v surgical/chemical), years since menopause, type of third-generation AI, or duration of AI therapy. Patients who were overweight (BMI, 25 to 30 kg/m2) were less likely to have AI-related joint pain compared with those who had a normal BMI (< 25 kg/m2) or were obese (BMI > 30 kg/m2). Both AI-related joint pain and stiffness were associated with prior taxane chemotherapy. Results of multiple logistic regression analysis for presence of AI-related joint pain/stiffness, controlling for sociodemographic, clinical, and treatment-related variables, are listed in Table 3. Women who were overweight (BMI, 25 to 30 mg/kg2) were less likely to experience AI-related joint pain (odds ratio [OR] = 0.33, 95% CI, 0.14 to 0.74) compared with women with a normal BMI (< 25 mg/kg2). However, obesity (BMI > 30 mg/kg2) did not confer a protective effect for joint pain. Women who had prior tamoxifen therapy were less likely to develop AI-related joint stiffness (OR = 0.40; 95% CI, 0.19 to 0.87) compared with those who did not receive tamoxifen. Interestingly, patients who received prior taxane-based chemotherapy were more than four times more likely than those who did not to report AI-related joint pain and stiffness (OR = 4.08; 95% CI, 1.58 to 10.57 and OR = 4.76; 95% CI, 1.84 to 12.28, respectively).
Treatment Strategies for AI-Related Arthralgia Of all patients who reported having either AI-related joint pain and/or stiffness (n = 106), 56 patients (53%) reported taking oral medications for symptom relief (Table 4). The main oral medications used included nonsteroidal anti-inflammatory drugs (52%), acetaminophen (30%), opiates (7%), and oral supplements, such as glucosamine, chondroitin, and omega fish oils (26%). Among patients who used oral medications to relieve their AI-related arthralgia, 78% reported moderate to complete relief of their joint symptoms. In addition, 49 women (46%) used nonpharmacologic interventions, mainly exercise, to relieve their joint symptoms.
We found that among postmenopausal breast cancer patients taking adjuvant AI therapy, about half of them reported joint symptoms that either developed or worsened after initiating AIs. After controlling for demographic and clinical characteristics, patients who were overweight and those who had prior tamoxifen therapy were less likely to report AI-related joint symptoms. Surprisingly, patients who received taxane chemotherapy were more than four times more likely to develop AI-related joint pain and stiffness compared with those who did not. AI therapy is the standard of care for postmenopausal women with both early- and late-stage hormone-sensitive breast tumors.2-4,6-8,17 The success of AIs as adjuvant treatment depends, however, on patients' ability and willingness to adhere to treatment. Studies show that despite the known benefits of tamoxifen, 23% to 40% of women discontinue therapy early.18,19 Although AIs are considered to have a better adverse effect profile compared with tamoxifen, significant musculoskeletal discomfort may lead to suboptimal adherence, and possibly reduced efficacy. A recent study analyzing medical and pharmacy claims data from three national longitudinal databases found that adherence to adjuvant anastrozole therapy decreased from 69% to 78% in year 1 to 50% to 68% in year 3.20,21 In large adjuvant trials involving AIs, the incidence of musculoskeletal disorders was 20% to 30%, and nearly 5% of patients discontinued therapy in the AI group because of toxic effects.2,3 The nature of the clinical trials is such that patients may be more prone to under-report this type of adverse effect. For example, Basch et al10 found higher agreement between patient and clinician reporting of adverse effects for symptoms that were directly observable compared with more subjective symptoms, such as fatigue and dyspnea, for which physicians under-reported symptoms. In another study, 16% of metastatic breast cancer patients complained of joint pain within 2 months of starting anastrozole and 5% had to discontinue therapy because of severe arthralgia.22 Discontinuation of anastrozole resulted in resolution of pain-related symptoms. The exact mechanism of AI-related arthralgia is unclear, but is believed to be related to estrogen deprivation. OA is a disease of joints, resulting in progressive and permanent articular cartilage degeneration.23 More than 80 years ago, Cecil and Archer24 first described "arthritis of the menopause" as the rapid development of hand and knee OA coinciding with cessation of menses. Furthermore, observational studies of the incidence and prevalence of OA in postmenopausal women with and without hormone replacement therapy (HRT) has provided strong support for a protective effect of estrogens in OA.25-27 HRT reduces the incidence of radiologic knee OA,28,29 and increases tibial cartilage volume.30 In a randomized controlled trial of HRT, the Heart and Estrogen/Progestin Replacement Study found no difference in the prevalence of knee pain with or without HRT (24.1% and 26.1%, respectively).31 However, another intervention trial, the Women's Health Initiative recently reported a difference in the incidence of any joint pain or swelling in postmenopausal women taking estrogen compared with those who were not taking estrogen (70.6% v 77.2%; P = .01).32 The identification of the two estrogen receptors alpha and beta in human articular chondrocytes provided additional evidence that cartilage is sensitive to estrogens.33-36 Various animal and in vitro studies suggest that estrogen may play a role in the regulation of cartilage turnover and development of joint disease. In an experimental model of postmenopausal OA with ovariectomized rats, estrogen deficiency accelerated cartilage turnover and increased cartilage surface erosion, whereas administration of estrogen or selective estrogen receptor modulators suppressed cartilage degradation significantly.37 Our observation of a protective effect of prior tamoxifen therapy on AI-related joint stiffness is consistent with these preclinical findings. Similarly, increased adiposity and hence increased sex hormone levels may explain the lower prevalence of AI-related joint pain in overweight women compared with women with a normal BMI. However, the protective effect was lost among obese women, perhaps due to the counterbalancing effect of an increased risk of OA with obesity. The clinical characteristics of AI-related arthralgias have not been well described.22 Morales et al38 examined 12 consecutive nonmetastatic breast cancer patients taking AIs who reported severe musculoskeletal pain. The authors reported characteristic tenosynovial joint changes on joint ultrasound and magnetic resonance imaging, which included fluid in the digital flexor tendon sheaths on ultrasound and tendon sheath enhancement and thickening on magnetic resonance imaging in their series.38 There currently are no validated measures to specifically assess AI-induced joint symptoms, which limits the interpretation of all studies of this entity. We were surprised to find a greater than four-fold increased risk of AI-related joint symptoms in patients who received prior taxane therapy. Musculoskeletal pain is a known adverse effect of taxane chemotherapy; however, reports of long-term adverse effects have been limited to peripheral neuropathy. It is unclear whether residual effects from taxane-induced musculoskeletal syndrome are being misclassified as self-reported joint symptoms due to AIs, or whether there is a synergistic effect between taxanes and AIs on drug-induced arthralgias. A potential limitation of this study is the cross-sectional design, which introduces the possibility of selection and recall bias. Selection bias was limited given that the participants were unaware of the study hypothesis at the time of enrollment and very few patients (2%) declined participation. For our primary outcome of AI-related joint symptoms, we relied on self-report. There may have been under-reporting of AI-related arthralgia, given that joint symptoms are common in postmenopausal women (68% of our total sample) and some patients may not attribute their joint symptoms to AI therapy. In addition, we only included women who were actively receiving adjuvant AI therapy, thus our survey did not capture women who discontinued therapy early due to adverse effects. Ten patients (5%) surveyed had switched from one third-generation AI to another due to intolerable adverse effects. Thus, our study may have underestimated the prevalence and severity of AI-related arthralgia. To our knowledge, this is the first report of the prevalence of AI-related arthralgia in the practice setting and potential risk factors associated with this drug-induced toxicity. Furthermore, this is the first report that symptoms may be exacerbated by prior taxane therapy. Additional research should assess the natural history and clinical characteristics of this drug-induced joint syndrome and interventions to alleviate these symptoms. The long-term effects of profound estrogen suppression in breast cancer patients taking AIs are unknown. Therefore, targeted interventions that relieve AI-induced musculoskeletal pain are needed. However, until interventions are identified, patients who suffer severe adverse effects should be reassured that the clinical benefit of AIs compared with tamoxifen is modest, so that for some, changing therapy may be a reasonable solution.
The author(s) indicated no potential conflicts of interest.
Conception and design: Katherine D. Crew, Heather Greenlee, Jillian Capodice, Dawn L. Hershman Financial support: Dawn L. Hershman Administrative support: Alex Sierra Provision of study materials or patients: Katherine D. Crew, George Raptis, Lois Brafman, Deborah Fuentes, Alex Sierra, Dawn L. Hershman Collection and assembly of data: Katherine D. Crew, Lois Brafman, Deborah Fuentes, Alex Sierra Data analysis and interpretation: Katherine D. Crew, Heather Greenlee, Jillian Capodice, Dawn L. Hershman Manuscript writing: Katherine D. Crew, Dawn L. Hershman Final approval of manuscript: Katherine D. Crew, Heather Greenlee, Jillian Capodice, George Raptis, Lois Brafman, Deborah Fuentes, Alex Sierra, Dawn L. Hershman
K.D.C. is the recipient of a Lance Armstrong Young Investigator Award. H.G. is the recipient of an R25 Award from the National Cancer Institute (CA94061). D.L.H. is the recipient of a K07 Award from the National Cancer Institute (CA95597), an Irving Scholar Award, and a research award from Women at Risk. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Nilsson LO, Boman A, Savendahl L, et al: Demonstration of estrogen receptor-beta immunoreactivity in human growth plate cartilage. J Clin Endocrinol Metab 84:370-373, 1999 37. Høegh-Andersen P, Tanko LB, Andersen TL, et al: Ovariectomized rats as a model of postmenopausal osteoarthritis: Validation and application. Arthritis Res Ther 6:R169-R180, 2004[CrossRef][Medline] 38. Morales L, Pans S, Paridaens R, et al: Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: Associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat [epub ahead of print on October 24, 2006] Submitted January 10, 2007; accepted March 28, 2007. Related Editorial
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests. Multivariate logistic regression models were created using presence of AI-related joint pain and stiffness as the dependent variables, and demographic, clinical, and treatment characteristics as independent variables. Data were analyzed using SAS (version 9.1; SAS Institute Inc, Cary, NC). 
