Estrogen deficiency after menopause has been linked to an increase in several chronic inflammatory conditions, including osteoporosis and osteoarthritis (OA) (Riggs and Melton 1992; Sherwin 1996). Estrogen can influence chondrocyte formation on multiple levels by interacting with cellular growth factors, adhesion molecules, and cytokines (Ushiyama et al. 1995; Rosner et al. 1982; Dayani et al. 1988). A dose-dependent change in matrix protein turnover occurs when cultured chondrocytes are exposed to estradiol (Richmond et al. 2000; Dayani et al. 1988; Blanchard et al. 1991; Rosner et al. 1982). Production of interleukin-6 (IL-6) and type II collagen in articular chondrocytes is also affected by estradiol, suggesting it may affect cartilage metabolism (Guerne et al. 1990; Claassen et al. 2006; Richette et al. 2003). Additional support that estrogen deprivation results in this syndrome comes from studies showing that hormone replacement with conjugated equine estrogens result in decreased joint pain, pain severity and joint swelling in postmenopausal women (Chlebowski et al. 2013).

In addition, there may be an autoimmune component to the syndrome. Animal models, where aromatase is knocked out, manifest symptoms similar to Sjögren’s syndrome. In a study of patients referred to a rheumatologist, 50 % met the criteria for sicca syndrome (Laroche et al. 2007). Several small studies have also evaluated the influence AI therapy on inflammatory serum markers but results evaluating CRP, IL-6, and TNFα have been inconsistent (Dougherty et al. 2005; Azria et al. 2007; Harputluoglu et al. 2008). Even in studies showing AI-related changes to inflammatory markers, these changes were not correlated with the development of AI arthralgia (Azria et al. 2007).

Studies assessing AI-induced arthralgias have shown a correlation between PROs and objective findings. Morales et al. demonstrated that the subjective symptoms of AI-induced arthralgias in the hands are associated with physiologic changes to joints and functional impairments (Morales et al. 2008). Women taking AIs are more likely to have an increase in tenosynovial changes as seen on MRI, a decrease in grip strength as measured by a sphygmomanometer, as well as increased pain and stiffness as measured by self-administered questionnaires (Morales et al. 2008). In a study conducted by Dizdar et al., women taking AIs had increased tendon thickness and higher rates of effusions in hand joints/tendons on musculoskeletal sonography, compared to women who never received AIs (Dizdar et al. 2009; Lintermans et al. 2011). AI use is also associated with a greater incidence of carpal tunnel syndrome of moderate intensity and short duration (Sestak et al. 2009). With regard to pain sensitivity, the syndrome does not appear to result in impairment of descending pain inhibitory pathways as measured by pressure pain testing or conditioned pain modulation testing (Henry et al. 2014).

The risk factors for developing AI-associated arthralgia are unclear. In some studies high BMI, prior chemotherapy, and a history of hormone replacement therapy are major risk factors for developing joint symptoms (Sestak et al. 2008). Other studies show prior taxane chemotherapy, symptoms at the time of treatment initiation and time from menopause are also associated with severity of AI arthralgias (Shi et al. 2013; Crew et al. 2007; Mao et al. 2011). One prospective cohort study found that additional risk factors for the development of pain included higher levels of anxiety and impaired quality of life at the time of initiation of therapy (Laroche et al. 2014).

The question of genetic susceptibility to toxicity has been addressed as well. In a prospective cohort study of 343 post-menopausal women starting AI therapy, single nucleotide polymorphisms (SNPs) in genes encoding for the metabolism of estrogens (CYP17A1) and vitamin D (VDR, CYP27B1) were associated with self-reported arthralgia (Garcia-Giralt et al. 2013). In addition, patients who had SNP’s for multiple genes had the highest risk for AI arthralgia. A cross-sectional study in 390 patients also found that repeats in the CYP19A1 gene were associated with AI arthralgias (Mao et al. 2011). A better understanding of genomic and clinical risk factors can help identify patients who can be targeted for specific interventions to prevent this syndrome. An ongoing ECOG prospective cohort study in 1,000 women evaluating genomic predictors of AI arthralgias and early AI discontinuation should further clarify this issue.

The use of a non-steroidal anti-inflammatory agent, or simply switching to an alternative AI, are common clinical approaches for patients experiencing significant arthralgias. Interestingly, approximately a third of patients will experience some improvement in symptoms by simply switching to another AI (Henry et al. 2012). There are, however, currently no proven treatments for AI-related arthralgias. Researchers have investigated interventions that have been studied in patients with chronic pain conditions, osteoarthritis and rheumatologic arthritis. Patients are often not willing to take medications to treat side effects, that have the potential for additional side effects, so many have gravitated to natural products, mind-body interventions and exercise. Many prospective trials are collecting blood and DNA to perform analysis that will be critical in elucidating the mechanism of this side effect as well as genetic susceptibility (Table 7.1).

Vitamin D deficiency and insufficiency may contribute to musculoskeletal symptoms. In a prospective study, 60 women who were beginning adjuvant AI therapy had baseline vitamin D (25OHD) levels measured. At the conclusion of 16 weeks of letrozole, 52 % of women with baseline 25OHD levels >66 ng/ml reported no disability from joint pain, whereas only 19 % of those with levels <66 ng/ml had no disabling joint pain (Khan et al. 2010). In a subsequent randomized VITAL trial (Vitamin D for Arthralgias From Letrozole), 160 postmenopausal women with a serum vitamin D level of <40 ng/mL were randomized to receive 30,000 IU of oral vitamin D3 weekly for 24 weeks; the other was given a placebo. About 61 % of controls and 38 % of those on vitamin D reported an increase in pain (P = .008) (Khan et al. 2012).

Glucosamine and chondroitin are popular dietary supplements frequently used with the goal of treating arthritic pain. In a non-randomized phase II trial of glucosamine and chondroitin to treat moderate-to-severe aromatase inhibitor induced joint pain, approximately 50 % of participants self-reported a ≥20 % improvement in pain, stiffness and function. The intervention was well-tolerated with minimal toxicities and no changes in estradiol levels were observed (Greenlee et al. 2013). Nonetheless, a placebo effect may be largely responsible for this finding.

Omega-3-fatty acids have anti-inflammatory effects and can be effective in decreasing arthralgias from rheumatologic conditions. A placebo-controlled trial of 3.3 g of Omega-3-fatty acids was conducted among 249 women on AIs with severe (≥5 of 10) pain and or stiffness. Interestingly a 60 % improvement was observed in the group randomized to Omega-3. However, a similar reduction was seen in the placebo arm. At 24 weeks, both groups had about a 2-point improvement from baseline on a 10 point scale (Hershman et al. 2014). This study demonstrates the difficulty in relying on patient-reported outcomes and the strength of the placebo effect. It also raises questions about the results of other trials where the intervention could not be truly blinded.

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor used for treating pain. A single-arm, open-label phase 2 study of duloxetine was studied in women with breast cancer who developed new or worsening pain after treatment with an AI. Twenty-one of twenty-nine evaluable patients (72.4 %) achieved at least a 30 % decrease in average pain. The mean percentage reduction in average pain severity was 60.9 % (Henry et al. 2011). Based on the results of this study, a randomized placebo-controlled trial is being conducted in SWOG.

A double blind placebo-controlled, randomized pilot study of a transdermal testosterone preparation supported that this approach was helpful for alleviating aromatase inhibitor-induced arthralgias (Birrell and Tilley 2009). This trial involved 90 patients with baseline AI arthralgia pain and/or stiffness be greater than 50 on a 0–100 point pain scale. Patients were randomized into one of three study arms to receive a low testosterone dose versus an intermediate testosterone dose versus a placebo. After 3 months, the pain scores decreased more in the intermediate dose testosterone arm compared to the placebo arm (P = 0.04). Likewise, stiffness scores decreased more in the intermediate dose testosterone arm, compared to the placebo arm (P = 0.06). While serum testosterone concentrations increased in the groups getting testosterone, there was no suggestion that estrogen concentrations were any higher with testosterone, compared to the placebo arm. Based on these promising findings a phase III randomized placebo-controlled trial, using intradermal testosterone pellets, is being conducted in women with AI arthralgias, through the Alliance cooperative group.

Autoimmune diseases are often treated with low dose steroids, and as mentioned above, there is some similarities between the arthralgia syndrome from AI’s and Sjögren’s syndrome. To test this approach, patients with AI arthralgia were administered 5 mg of oral prednisolone once a day in the morning for only 1 week. Patients were then asked to answer a questionnaire about joint pain symptoms at 1 week, 1 month and 2 months after the beginning of prednisolone use. Joint pain symptoms improved in 67 % of patients immediately after prednisolone use, with 63 % still reporting analgesic effect at 1 month, and 52 % at 2 months after beginning the short-term use of prednisolone (Kubo et al. 2012).

Acupuncture is a popular non-pharmacologic modality that has been shown to be a useful adjunct in a range of painful conditions, including musculoskeletal pain (Anonymous 1998). Small pilot trials for AI arthralgias have reported conflicting results. A randomized, sham-controlled, blinded trial to assess the effect of a 6-week intervention of acupuncture in 38 women with AI-associated joint symptoms reported that true acupuncture group had a 50 % decrease pain compared to no change in the sham acupuncture group (Crew et al. 2010). Other smaller studies have suggested a benefit of both standard and electroacupuncture (Oh et al. 2013; Mao et al. 2014). A larger multicenter randomized trial with a waitlist control, sham, and true acupuncture is being conducted in SWOG.