Aromatase inhibitors (AIs), the adjuvant hormonal treatment of choice for postmenopausal estrogen receptor-positive breast cancer, are associated with an increased risk of musculoskeletal symptoms. The underlying cause of the symptoms is often attributed to estrogen depletion, yet all women treated with AIs have low estrogen levels and only a subset develop symptoms. Concentrations of circulating androgens may be mediating factors contributing to these side effects. The purpose of this study was to examine changes in androgen concentrations among women initiating AI therapy and to determine if concentrations are associated with musculoskeletal symptoms. Data were analyzed from a cohort study of 74 breast cancer patients for whom AI therapy was planned. Questionnaire data on symptoms were collected and blood was drawn prior to AI therapy (baseline) and then again at 3 and 6 months after baseline. Blood was assayed for testosterone, androstenedione, dehydroepiandrosterone-sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Free testosterone index (FTI) values were calculated using testosterone and SHBG measurements. The results showed that concentrations of all of the androgens increased over the study period, with statistically significant differences from baseline concentrations observed for the FTI at 3 and 6 months and for DHEAS at 6 months. Additionally, breast cancer patients with new onset or worsening of pain over the study period had a significantly smaller change in mean DHEAS concentration from baseline to 3 months (P = 0.04) and a marginally significant smaller change in mean DHEAS concentration from baseline to 6 months (P = 0.1) compared to those who reported no pain at all time points or no worsening of pain across the study period. Changes in testosterone, androstenedione, and the FTI were not associated with the onset or worsening of pain during the study period. Findings from this study suggest that higher DHEAS concentrations are associated with less AI-associated pain and should be further investigated.

Because bothersome symptoms and side-effects are a major reason for discontinuation and non-adherence to treatment, symptoms should be monitored and addressed by oncologists so that the breast cancer patient can maintain her quality of life and remain adherent to the treatment schedule.

This study compared type, severity and location of musculoskeletal symptoms and associations with 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) concentrations between women initiating aromatase inhibitor (AI) therapy and an unexposed comparison group. A 6-month prospective cohort study was conducted, enrolling 100 breast cancer patients prior to initiating AI treatment and an unexposed comparison group of 200 postmenopausal women. Multivariate associations were assessed with generalized linear models. At baseline, 55% of breast cancer patients and 63% of the comparison group reported any musculoskeletal symptoms. Among the unexposed group, prevalence and severity of symptoms remained constant with no statistically significant change over 6 months. Among breast cancer patients, but not unexposed women, the pain severity score significantly increased over the 6 month period for joint (P (trend) < 0.001), muscle (P (trend) = 0.004), and bone pain (P (trend) = 0.01). Women treated with AIs were more likely to report pain in wrists/palms (63% at 6 months) compared to unexposed women (31% at 6 months) (P < 0.001). 25(OH)D concentrations increased over the study period among breast cancer patients (P (trend) = 0.004). An increase in pain severity and prevalence was observed among breast cancer patients despite an increase in 25 (OH)D concentration. CRP concentrations were not associated with symptoms. Musculoskeletal symptoms are common among postmenopausal women. Breast cancer patients initiating AI treatment were at increased risk for developing new onset and more severe joint, muscle and bone pain compared to unexposed women, with a distinct distribution. AI-associated symptoms were not associated with 25(OH)D or CRP concentrations.

The objectives of this study were to examine 1) changes in bone formation (osteocalcin) and bone resorption [cross-linked N-telopeptides of bone type I collagen (NTXs)] markers, as well as calcium, phosphorus, and intact parathyroid hormone, over the first 6-months of aromatase inhibitor (AI) therapy among a cohort of breast cancer patients compared to a group of unexposed women without a history of cancer; and, 2) whether bone marker changes were associated with musculoskeletal pain. Eligible breast cancer patients (n=49) and postmenopausal women without a history of cancer (n=117) were recruited and followed for 6-months. At baseline, 3-months, and 6-months, a questionnaire was administered to assess pain and medication use and a blood sample was drawn. Results showed that, among the breast cancer patients, calcium concentrations decreased significantly (-7.8% change; p=0.013) and NTXs concentrations increased significantly from baseline to 6-months (9.6% change; p=0.012). Changes were not observed for women in the comparison group. Statistically significant differences in percent change between the breast cancer patients and the women in the comparison group were observed for calcium at 6-months (-7.8% versus 0.0%; p=0.025), phosphorus at 6-months (-5.1% versus 16.7%; p=0.003), NTXs at 6-months (9.6% versus -0.7%; p=0.017), and osteocalcin at 6-months (11.5% versus -3.6%; p=0.016). No statistically significant associations were observed between bone turnover marker changes and musculoskeletal pain among the breast cancer patients, although baseline NTXs were higher among women with onset or increase in pain compared to those reporting no pain (p=0.08). Findings from this study suggest that AIs cause changes in bone turnover during the first 6-months of treatment; however, these changes are not associated with musculoskeletal pain. Breast cancer patients initiating AI therapy should be assessed and monitored for fracture risk using known clinical risk factors, including bone density, and managed appropriately.

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