Aromatase inhibitors (AIs) have become first-line standard adjuvant endocrine therapy for postmenopausal women with hormone receptor positive (HR+) breast cancer. Although outcomes have improved compared to tamoxifen(1), AI therapy has been associated with significant, activity-limiting musculoskeletal symptoms including arthralgia, myalgia, and joint stiffness, collectively called AI-associated arthralgias (AIA)(2,3). Among the most commonly reported side effects experienced by patients on AI therapy are musculoskeletal-related symptoms including joint pain and joint stiffness, with up to 50% of women reporting joint-related symptoms(4,5). Musculoskeletal-related symptoms manifest early after initiation of AI therapy and worsen for up to 1 year(6,7). A number of studies have revealed high discontinuation of AIs (31–73%) and low adherence (41–72%) after 5 years(8). A large observational study (
Imaging studies using ultrasound (US) and magnetic resonance imaging (MRI) of hands/wrists to determine physiological changes and biomarkers associated with AIA show ambiguous results. While some demonstrate increased tendon thickness and fluid among women on AIs(12,13), other studies have shown no such difference(14,15). Morales
Shear wave elastography (SWE) is a novel US technique for characterizing tissue structures with shear acoustic waves of a focused ultrasonic beam(19) to acquire a measure of tendon stiffness. We conducted a pilot study to evaluate tendon features of the hands and wrists using SWE US imaging in postmenopausal women on AIs with AIA versus healthy controls. Since tendinopathic tendons have decreased SW velocities (i.e. are softer) compared to healthy normal tendons(20), we hypothesized that women with AIA would have softer tendons than controls. To our knowledge, this is the first study to utilize SWE in the context of AIA.
This study was approved by the University of Arizona Institutional Review Board, and all participants provided written informed consent (IRB# 1404308335). The enrolled subjects were stage I–II breast cancer patients that were treated at the University of Arizona Cancer Center (UACC) with a non-steroidal AI for their adjuvant therapy and complained of joint pain (
Real-time gray-scale and power Doppler US examination of bilateral wrists and hands were performed on a General Electric Logiq E9 machine using the 18–8 MHz linear hockey stick transducer per our routine inflammatory arthritis protocol. Dorsal and volar aspects of the 2nd, 3rd, and 5th metacarpophalangeal (MCP) joints were examined in their long and short axes. Additionally, all six extensor compartment tendons and tendon sheaths, as well as flexor tendons in the carpal tunnel and the median nerve, were examined in their long and short axes. US examination of the flexor and/or extensor tendons was performed along the digits/fingers.
During US examination, patients were seated with their hands resting on a small table placed between the examiner and the patient. All joints were examined for the presence of cortical erosions on gray-scale US. All joints, tendons, and tendon sheaths were evaluated for the presence of increased synovial fluid complex on gray-scale evaluation and for the presence of hyperemia on power Doppler evaluation. We also examined the median nerve for hyperemia, and patients were asked whether they experienced pain, numbness, tingling, or muscle weakness in the palm, thumb, index, middle or little fingers (“symptomatic” findings). In addition, the presence or absence of soft tissue edema was recorded. Results for each finding were scored as present (1) or absent (0).
SWE US examinations of the bilateral wrists and hands were then performed on a Siemens S3000 unit (Siemens Medical Systems) with a high-resolution 9-MHz linear transducer. The tissue elasticity (degree of stiffness) was displayed on color bar elastogram on the US screen and expressed as SW velocities in m/s. A copious amount of ultrasound gel was used to accommodate the depth. The radial aspect of the 2nd and 3rd MCP joints and the ulnar aspect of the 5th MCP joints were examined in their long axes.
At the dorsal aspect of each wrist and hand, SWE of all six extensor compartment tendons was performed in the long and short axes. At the volar aspect of each wrist, SWE of the flexor tendons and the median nerves was performed, centered in the carpal tunnel region. SWE of the flexor and extensor tendons was performed along the digits/fingers.
Ultrasound B-mode DICOM images taken by the Siemens ACUSON S3000 were examined by a trained radiologist to determine regions of interest (ROIs) containing anatomical structures of interest: the 1st, 2nd, 4th, and 6th extensor compartments; the 2nd, 3rd, and 5th MCP joints; the median nerve; and the volar flexors adjacent to the median nerve. The B-mode images were co-registered with SW velocity color maps. Depending on the size, each ROI contained 6,000–20,000 pixels; the average SW velocity of all the pixels contained within each ROI was calculated using color map values and tabulated. Each compartment contains multiple tendons (except the 6th). When compartments are imaged along the short axis, multiple tendons are captured within an ROI; therefore, the reported SWE velocities represent an average of multiple tendons in a given compartment. For the longitudinal collection of the compartments, one representative tendon was chosen by the radiologist for scoring.
Ages of the healthy controls and AI patients were compared using a two-sample independent t-test. Fisher’s exact test was used to assess between-group differences in characteristics determined by US imaging. Between-group differences in SW velocity was determined using linear mixed models, initially clustered on participant and then further adjusted for area of the ROI. A
The mean age of healthy controls was 59.3 years (range 54–72 y) which was not different from the mean age of breast cancer patients on AI at the time of imaging (60.0 y, range 45–70 y; t-test
Characteristic |
|
---|---|
Age at diagnosis: |
58 (43–69) y |
Surgery | |
• Lumpectomy | 4 (67%) |
• Mastectomy | 2 (33%) |
Adjuvant radiation therapy | 4 (67%) |
Adjuvant chemotherapy | 2 (33%) |
Stage | |
• I | 4 (67%) |
• II | 2 (33%) |
Duration on AI:
1
|
13.2 (4–20) months |
Duration on an aromatase inhibitor before ultrasound imaging
Table 2 shows presence or absence of abnormal imaging findings at the MCP joints, wrists, flexor and extensor tendons, and the median nerve using gray-scale and power Doppler US. There were no significant differences in increased joint fluid, hyperemia, or cortical irregularity between controls and the AI group. In the median nerve, there were no significant differences in the presence of hyperemia, symptomatic findings, or bifid anatomy. Taken together, 7 of 7 controls had all negative median nerve findings (no hyperemia, not symptomatic, not bifid) compared to 2 of 6 in AI group;
Clinical site and finding | Control | AI |
|
---|---|---|---|
MCP joints | |||
• Increased joint fluid | 0/7 (0%) | 2/6 (33%) | 0.19 |
• Hyperemia | 0/7 (0%) | 2/6 (33%) | 0.19 |
• Cortical irregularity | 0/7 (0%) | 0/6 (0%) | n/a |
• All above negative | 7/7 (100%) | 4/6 (67%) | 0.19 |
Wrists | |||
• Increased joint fluid | 1/7 (14%) | 3/6 (50%) | 0.27 |
• Hyperemia | 0/7 (0%) | 1/6 (17%) | 0.46 |
• Cortical irregularity | 0/7 (0%) | 1/6 (17%) | 0.46 |
• All above negative | 6/7 (86%) | 3/6 (50%) | 0.27 |
Flexor & extensor tendons | |||
• Increased Tenosynovial fluid | 0/7 (0%) | 3/6 (50%) | 0.07 |
• Hyperemia | 0/7 (0%) | 3/6 (50%) | 0.07 |
• All above negative | 7/7 (100%) | 3/6 (50%) | 0.07 |
Median nerve | |||
• Hyperemia | 0/7 (0%) | 1/6 (17%) | 0.46 |
• Symptomatic | 0/7 (0%) | 3/6 (50%) | 0.07 |
• Bifid | 0/7 (0%) | 3/6 (50%) | 0.07 |
• All above negative | 7/7 (100%) | 2/6 (33%) | 0.02 |
MCP – metacarpophalangeal
Fisher’s Exact Test
Figure 1 illustrates representative SW US images from the 1st extensor compartment (A, B), the median nerve (C, D), the volar flexor (C, D), and the MCP joint (E, F) from patients on AI (left panels) and control subjects (right panels). The SW velocity is represented by a color scale such that blue is the slowest (0 m/s; least stiff) and red is the fastest (15 m/s; most stiff). Faster SW velocities can be visualized for AI tendons versus control. Figure 2 illustrates the grayscale images of the locations imaged in Fig. 1 in order to assist visualization of the anatomical sites.
Table 3 presents the velocity determined by SWE, where a faster velocity indicates stiffer tendons. The 1st extensor compartment tendons and tendon sheaths were significantly stiffer in postmenopausal women on AI than controls in both the long (
Imaqe location | AI | CL | Model 1 b | Model 2 c | ||||
---|---|---|---|---|---|---|---|---|
|
median (IQR) |
|
median (IQR) | beta |
|
beta |
|
|
1st Extensor compartment (long axis) d,e | 5 | 8.52 (7.45–10.26) | 5 | 5.70 (4.84–7.14) | 3.57 | 0.001 | 3.40 | 0.003 |
1st Extensor compartment (short axis) f,e | 4 | 5.51 (5.42–7.89) | 4 | 4.37 (3.71–5.34) | 2.28 | 0.061 | 2.79 | 0.036 |
2nd Extensor compartment (short axis) e | 4 | 5.36 (4.69–6.67) | 4 | 4.99 (3.94–6.09) | 0.53 | 0.586 | 0.69 | 0.445 |
4th Extensor compartment (long axis) e | 5 | 7.12 (6.78–7.94) | 7 | 5.82 (5.14–7.76) | 1.42 | 0.014 | 1.20 | 0.039 |
6th Extensor compartment (long axis) | 5 | 9.53 (7.78–12.95) | 6 | 9.32 (8.09–11.5) | 1.15 | 0.441 | 1.12 | 0.456 |
2nd MCP (radial dorsal image) g | 6 | 5.86 (4.78–6.39) | 5 | 4.78 (4.39–5.00) | 0.84 | 0.220 | 0.75 | 0.276 |
3rd MCP (radial dorsal image) | 6 | 6.37 (5.09–8.31) | 5 | 4.60 (3.81–4.61) | 2.79 | 0.002 | 1.89 | 0.008 |
5th MCP (ulnar dorsal image) h | 5 | 5.22 (4.68–6.55) | 5 | 4.61 (4.28–4.80) | 1.12 | 0.093 | 1.16 | 0.083 |
Median nerve | 6 | 4.60 (4.29–4.88) | 7 | 4.89 (3.46–6.20) | –0.68 | 0.549 | –0.80 | 0.183 |
Volar flexors (long axis) | 6 | 8.31 (6.47–8.93) | 7 | 8.76 (7.41–9.82) | –0.07 | 0.956 | –0.12 | 0.927 |
Extensor compartments pooled (long axis) i | 5 | 8.83 (7.57–10.26) | 7 | 7.44 (5.82–11.6) | 1.62 | 0.044 | 1.74 | 0.040 |
Extensor compartments pooled (short axis) j | 4 | 5.73 (5.26–5.95) | 4 | 5.13 (4.11–5.44) | 1.40 | 0.035 | 1.40 | 0.032 |
Synovial fluid complexes of the MCP joints pooled k | 6 | 5.46 (5.09–6.34) | 5 | 4.80 (4.28–4.94) | 1.73 | 0.002 | 1.30 | 0.011 |
Volar flexors pooled (long + short axis) l | 6 | 8.76 (7.41–9.82) | 7 | 8.76 (7.41–9.82) | –0.09 | 0.941 | 0.07 | 0.952 |
Not all anatomical images were available for all participants. Anatomical locations were analyzed separately if they were captured in at least 4 AI patients and 4 controls. Images were analyzed from the left, right, or both hands if available.
Linear mixed model of velocity, clustered on person; n is the number of people, not the number of hands
Linear mixed model of velocity, adjusted for area, clustered on person
Long axis images were acquired along the longitudinal section of the anatomical site
SWE velocities were averaged for all tendons within each compartment
Short axis images were acquired along the cross-section of the anatomical site
Radial images were acquired on the same side as the radius
Ulnar images were acquired on the same side as the ulna
Includes 1st, 2nd, 4th, and 6th extensor compartments – all longitudinal axis images
Includes 1st, 2nd, 4th, and 6th extensor compartments – all cross-sectional images
Includes 2nd, 3rd, and 5th MCP radial images + 2nd, 3rd, and 5th MCP ulnar images
Includes both longitudinal and cross-sectional images of the volar flexors
In light of recent evidence supporting extended adjuvant AI treatment to 10 years, the need to understand the pathophysiology of AIA is even more important in order to improve adherence over a longer duration of treatment(21). Our pilot data suggest that AIA is partially characterized by the presence of increased tendon stiffness compared to age-comparable, healthy women. To our knowledge, this is the first clinical study to evaluate tendon stiffness in breast cancer patients on AI utilizing SWE.
SWE is a robust, noninvasive technique to quantify tissue stiffness and identify tendon pathology at different locations, and it has been shown to significantly improve the diagnostic accuracy of traditional tendon US examination(20). Multiple studies suggest that tendinopathic tendons (including rheumatoid arthritis) have decreased SW velocities compared to healthy normal tendons(20,22). However, our results suggest that women with AIA have stiffer tendons and increased SW velocities than age-comparable healthy women. These differences could be related to the depletion of estrogen with AI treatment. One study reported that during the follicular phase of the menstrual cycle, muscles were significantly stiffer (evaluated by SWE) than during ovulation(23). This greater muscle stiffness during the follicular phase was associated with significantly lower estradiol than during ovulation. To our knowledge, however, no studies have evaluated tendon or joint stiffness in relationship to estradiol levels. In addition, it is also possible that the stiffer tendons and joints observed in the AIA group in the current pilot study are due to factors that were not controlled, such as occupation, BMI, or diet. Nevertheless, given that AI treatment has also been shown to increase the risk of rheumatoid arthritis(24), this study provides preliminary evidence supporting SWE as a valuable, objective modality to help understand the physiology of AIA and to distinguish it from other causes of joint pain, such as rheumatoid arthritis or osteoarthritis. Importantly, SWE was able to detect differences in tendon stiffness between AI patients and controls, whereas routine US examination was not.
We were limited by a very small sample size, cross-sectional design, and lack of asymptomatic women taking AI. Therefore, it is unknown if our observation that patients with AIA have stiffer tendons is a result of AI treatment alone, or if stiffer tendons are specific to those at risk for arthralgias. Furthermore, it is possible that selection bias led to differences between groups (e.g. socioeconomic status, occupation), which were not evaluated in this study and could be responsible for the observed differences. It is also possible that our observed differences are due to chance given our very small samples size. All
To our knowledge, we are the first to identify increased tendon stiffness as an imaging biomarker of AIA. Despite its limitations, this pilot study provides the first reported evidence supporting future prospective studies to determine whether tendon stiffness is a risk factor for the development of AIA, a result of AI treatment, or both.