Aromatase Inhibitor-associated Musculoskeletal Symptoms Research Articles

Abstract PO1-11-06: Evaluating Symptom Clusters in Patients with Breast Cancer Experiencing Aromatase Inhibitor-Associated Musculoskeletal Symptoms

Abstract Background: Although treatment with an aromatase inhibitor (AI) for 5-10 years decreases 10-year breast cancer mortality by about 40%, up to 25% of patients will stop treatment early because of treatment-related, intolerable joint and muscular pain and stiffness, called aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). We previously identified that nociplastic pain, or chronic pain in the absence of tissue damage or inflammation, is associated with increased likelihood of developing AIMSS. Other studies have found that symptom clusters, such as the SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy/fatigue) are prevalent and co-occur in patients with cancer. Here we examine the prevalence of SPPADE symptoms for patients experiencing AIMSS and willing to enroll on a clinical trial examining use of cannabidiol (CBD) to treat their symptoms. Methods: Patients with stage 0-3 hormone receptor-positive breast cancer experiencing AIMSS (defined as worst joint pain ≥4/10 during prior 7 days that developed or worsened since starting AI therapy) were eligible for enrollment in this single arm, single center phase 2 open label clinical trial (NCT04754399). Enrolled patients completed validated questionnaires at baseline and then received CBD (Epidiolex) for 15 weeks. Patient-reported outcomes (PRO) data was collected serially, including the following questionnaires which addressed SPPADE symptoms: Brief Pain Inventory (BPI) to assess pain, PROMIS Profile 29+2 v2.1 to assess multiple symptoms, and Fibromyalgia Survey (FMS) to assess nociplastic pain. Results: 39 patients enrolled on this clinical trial. The median age at enrollment was 57 (range 37-59) and 21% of patients were over age 70. The majority of patients were white (92%) and average BMI was 31 (SD 6.6). Anastrozole was the most used aromatase inhibitor (74%), followed by exemestane (18%), and letrozole (8%). 5 patients (13%) required concomitant GnRHa therapy. Baseline PRO data was obtained from 37 patients. BPI average pain score over the week prior to enrollment was 5.1 (SD 1.5) and worst pain score was 7.2 (SD 1.3). Pain interference reported on the BPI was 4.1 (SD 2.1). Compared to the general population, enrolled patients reported better physical function (T-score 60.2, SE 3.7), less depression (T-score 45.5, SE 4.7) and fatigue (T-score 46.7, SE 5.1), and similar levels of anxiety (T-score 51, SE 7.1) and sleep disturbance (T-score 49.5, SE 5.9) on the PROMIS Profile. On the FMS, 62% of patients had evidence of nociplastic pain, with average score 13.3 (SD 5.7). The median number of sites of pain in the body reported by patients was 8 (range 1-16). Conclusions: While patients enrolling on an AIMSS clinical trial reported a high degree of daily pain that regularly interferes with their activities, for most patients these symptoms did not appear to have a negative impact on mood, affect, or other symptoms that typically cluster with pain. Though it is difficult to extrapolate results from a small population, the unexpected absence of co-occurring symptoms in this population raises additional questions about the interplay of AIMSS and other symptoms commonly reported in interventional AIMSS studies. Follow-up PRO data will be obtained in this clinical trial, allowing us to examine the impact of CBD use on pain, pain interference, and other patient-reported symptoms, as well as to explore which patients are more likely to obtain benefit from CBD treatment. Funding support provided by Conquer Cancer, the ASCO Foundation and the Rising Tide Foundation for Clinical Cancer Research. Citation Format: Fleege Nicole, N. Lynn Henry. Evaluating Symptom Clusters in Patients with Breast Cancer Experiencing Aromatase Inhibitor-Associated Musculoskeletal Symptoms [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-06.

A Cohort Study to Evaluate Genetic Predictors for Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS): Results from ECOG-ACRIN E1Z11.

Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS) are common and frequently lead to AI discontinuation. Single nucleotide polymorphisms (SNPs) in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate associations between 10 SNPs and AI discontinuation due to AIMSS. Postmenopausal women with stage I-III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcomes (PRO) to assess AIMSS (Stanford Health Assessment Questionnaire; HAQ) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS, and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial strata provided 80% power to detect an effect size of 1.5-4. SNPs were in ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). Of 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. While more Black and Asian women developed AIMSS compared to White women (49% vs 39%, p=0.017; 50% vs 39%, p=0.004, respectively), AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population, or in distinct cohorts. The odds ratio for rs2296972 (HTR2A) approached significance for developing AIMSS. We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, PRO predictors of AIMSS, and differences by race.

Association of single nucleotide polymorphism of ERα gene and aromatase inhibitor-associated musculoskeletal symptoms

Association of single nucleotide polymorphism of ERα gene and aromatase inhibitor-associated musculoskeletal symptoms

Effectiveness of intervention for aromatase inhibitor-associated musculoskeletal symptoms: A protocol for systematic review and meta-analysis.

Background:Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are among the most common prominent side effects in patients using aromatase inhibitors (AIs) for breast cancer. Muscle and joint pain, morning stiffness, arthritis, and bone loss are common clinical symptoms in individuals. Traditional Chinese medicine (TCM) has been demonstrated to be useful in the treatment of AIMSS in previous investigations, although the sample sizes were limited, and systematic reviews were inadequate. The effectiveness and safety of TCM in the treatment of AIMSS will be investigated in this study.Methods:Randomized controlled trials from January 2010 to October 2021 were limited to English or Chinese. We searched PubMed, EMBASE, Cochrane Library, Web of Science, Medline, China Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang database, and the VIP database. Two researchers reviewed the literature and retrieved the data independently. Review Manager V5.3.was used to conduct the statistical analysis.Results:This systematic review and meta-analysis presents the most recent data on the use of TCM to treat AIMSS and offers a scientifically sound foundation for therapeutic practice. Upon completion, the findings will be submitted to a peer-reviewed journal.Ethics and dissemination:As the systematic review protocol did not involve human subjects, ethical approval was not required.PROSPERO registration number:CRD42020192553.

Predictors of Pain Reduction in Trials of Interventions for Aromatase Inhibitor-Associated Musculoskeletal Symptoms.

BackgroundAlmost one-half of aromatase inhibitor (AI)–treated breast cancer patients experience AI-associated musculoskeletal symptoms (AIMSS); 20%-30% discontinue treatment because of severe symptoms. We hypothesized that we could identify predictors of pain reduction in AIMSS intervention trials by combining data from previously conducted trials.MethodsWe pooled patient-level data from 3 randomized trials testing interventions (omega-3 fatty acids, acupuncture, and duloxetine) for AIMSS that had similar eligibility criteria and the same patient-reported outcome measures. Only patients with a baseline Brief Pain Inventory average pain score of at least 4 of 10 were included. The primary outcome examined was 2-point reduction in average pain from baseline to week 12. Variable cut-point selection and logistic regression were used. Risk models were built by summing the number of factors statistically significantly associated with pain reduction. Analyses were stratified by study and adjusted for treatment arm.ResultsFor the 583 analyzed patients, the 4 factors statistically significantly associated with pain reduction were Functional Assessment of Cancer Therapy Functional Well-Being greater than 24 and Physical Well-Being greater than 14 (higher scores reflect better function), and Western Ontario and McMaster Universities Osteoarthritis Index less than 50 and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands less than 33 (lower scores reflect less pain). Patients with all 4 factors were greater than 6 times more likely to experience at least a 2-point pain reduction (odds ratio = 6.37, 95% confidence interval = 2.31 to 17.53, 2-sided P < .001); similar results were found for secondary 30% and 50% pain reduction endpoints.ConclusionsPatients with AIMSS who have lower symptom and functional distress at study entry on AIMSS intervention trials are more likely to experience meaningful pain reduction. Baseline symptom and functional status should be considered as stratification factors in future interventional trials.

Prospective validation of genetic predictors of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) in a racially diverse cohort: Results from ECOG-ACRIN E1Z11.

12003 Background: AIMSS are common and frequently lead to early discontinuation of adjuvant AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes have been associated with AIMSS and AI discontinuation. The primary objective of E1Z11 was to validate previously identified associations between 10 specific SNPs in candidate genes and AI discontinuation due to AIMSS in a community-based, racially diverse cohort. Methods: Postmenopausal women with hormone receptor-positive stage I-III breast cancer enrolled onto a prospective multi-site cohort study, the majority through the NCI Community Oncology Research Program (NCORP). Participants received anastrozole 1 mg oral daily, and completed patient-reported outcomes (PROs) at baseline, 3, 6, 9, and 12 months. AIMSS was defined as &gt;20% increase in Stanford Health Assessment Questionnaire (HAQ) score over baseline occurring within 1 year of AI therapy. We projected 40% would develop AIMSS and 25% would discontinue AI treatment within 1 year, informing a planned enrollment of 1000 women with a fixed number per strata (600 Caucasian, 200 African-American [AA] &amp; 200 Asian) to provide 80% power to detect an effect size of 1.5-4. SNPs include ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). Hardy-Weinberg equilibrium (HWE) was evaluated within each racial subset. SNP genotypes were coded as additive effects on the log odds ratio by coding as 0, 1 or 2 for the count of the minor allele. A Cochran-Armitage trend test was used with a 1-sided alpha of 0.0025 (Bonferroni correction for 10 tests). Results: We enrolled 999 evaluable women (616 Caucasian, 184 AA, 199 Asian). Genotyping was successful in 974 (98%). AIMSS developed in 43%, and AI therapy was discontinued in 12% within 1 year. While more AA and Asians developed AIMSS compared to Caucasians (48% vs 38%, p=0.017; 50% vs 38%, p=0.004), AI discontinuation rates were similar across racial groups. HWE was satisfied for all SNPs at the 5% alpha level, except for TCL1A/rs11849538 (p=0.002) in the AA cohort. None of the 10 SNPs were significantly associated with AI discontinuation or development of AIMSS in the overall population, or in any of the 3 cohorts. Conclusions: Although AIMSS were more common in AA and Asians, AI discontinuation rates were similar in the 3 cohorts. We were unable to prospectively validate 10 SNPs in 4 genes previously associated with AI discontinuation due to AIMSS. Future analyses will include other predictors of AIMSS, PROs, and additional genetic markers for the entire cohort and by race. Support: NCI UG1CA189828, UG1CA233196, UG1CA233277, UG1CA233320, UG1CA233178, UG1CA233160, UG1CA232760, UG1CA233341, UG1CA233329, U10CA180821, UG1CA189821, UG1CA189830, U10CA180888, UG1CA189859, UG1CA189863, UG1CA189971. Clinical trial information: NCT01824836.

Adverse Events and Perception of Benefit From Duloxetine for Treating Aromatase Inhibitor-Associated Arthralgias.

BackgroundDuloxetine effectively treats aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) in women with breast cancer but causes low-grade toxicities. This secondary analysis examines the relationship between adverse events (AE) and patient-perceived benefit, based on patient self-report that the treatment received was beneficial despite side effects. We hypothesized that duloxetine had a favorable effect on patient-perceived benefit, even among duloxetine-treated patients who experienced AEs and who, had they been treated with placebo, would have experienced none.MethodsPrincipal stratification was used to estimate the effect of duloxetine vs placebo on patient-perceived benefit and Functional Assessment of Cancer Therapy-Endocrine Scale functional quality of life in the randomized, double-blind trial SWOG S1202 (n = 289). Subgroups of patients were defined by observed and counterfactual (what would have occurred had they been randomly assigned to the opposite study arm) experiences of AEs and the original primary outcome, reduction of average pain after 12 weeks of at least 2 points on the Brief Pain Inventory-Short Form.ResultsDuloxetine caused an estimated 23.4% (95% credible interval [CI] = 13.4% to 33.7%) of patients to experience an AE even though they would have experienced none on placebo. Those patients remained more likely to report that their received treatment was beneficial than comparable patients assigned placebo (73.3% vs 41.8%, respectively; 95% CI for difference = 15.4 to 47.2 percentage points), although there was no statistically significant effect of duloxetine on functional quality of life (11.3 vs 9.0, 95% CI for difference = -2.2 to +6.7).ConclusionDuloxetine resulted in higher patient-perceived benefit, even among those who would have an AE on duloxetine but none on placebo. Treatment of AIMSS with duloxetine should be considered for appropriate patients.

Early-stage breast cancer (BC) patients: Factors associated with aromatase inhibitor-induced musculoskeletal symptoms.

525 Background: Hormone receptor positive (HR+) breast cancer comprises the largest subgroup of breast cancer. Aromatase Inhibitors (AI) are a key treatment for HR+ BC patients (pts) and reduce mortality. Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness, occur in up to 50% of pts leading to low adherence to and often discontinuation of therapy. Little is known of the mechanism of AIMSS or its predisposing risk factors. This study aims to identify risk factors associated with AIMSS development in BC patients on AI therapy. Methods: We conducted a medical record review of pts with non-metastatic HR+ BC on adjuvant AI therapy between January 2009 and June 2017 at the University of Maryland Comprehensive Cancer Center. This study included 194 ptswho were free of arthralgia prior to AI therapy. We analyzed pts’ demographics, lifestyle factors, reproductive history, tumor characteristics, medications, cancer treatment, co-morbidities, AI type, onset and severity of AIMSS. Severe AIMSS was defined as requiring change in AI therapy or discontinuation. Multivariable-adjusted logistic regression was used to identify risk factors for severe AIMSS. Results: The mean age of participants was 61. The mean BMI at diagnosis was 30 kg/m2. 41% of pts were White, 40% were Black, 7% other and 12% unknown. Most (79%) did not have a history of tamoxifen and 16% were on GnRH agonists. Most (71%) used letrozole as initial AI therapy; 18% anastrozole; and 11% exemestane. 56% experienced AIMSS while on AI therapy and 20% required change or hold of AI therapy. 4% permanently discontinued AI due to AIMSS severity. BMI at diagnosis was significantly positively associated with risk of AIMSS. Multivariate odds ratio (95% confidence intervals) comparing the highest to lowest tertile of body mass index (BMI) at diagnosis was 4.01 (1.07-10.90; Ptrend: 0.05). There were no significant associations with race, smoking, reproductive factors, type of AI therapy, tamoxifen use prior to AI therapy, medication use, experience of other cancer treatments, and tumor characteristics. Conclusions: 56% of BC pts on adjuvant AI therapy experienced AIMSS. 24% of these changed, held or discontinued AI regimen due to severe AIMSS. Higher BMI at diagnosis was associated with a higher risk of AIMSS. Our results confirm clinical significance of AIMSS among BC pts on AI therapy and suggest BMI as a modifiable factor for AIMSS. A larger study is warranted to replicate our findings and seek other possible risk factors for AIMSS.

Abstract P5-12-13: Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients

Abstract Introduction: Aromatase Inhibitors (AI) are a mainstay of treatment for hormone receptor positive breast cancer (BC) in postmenopausal women. However, patients under AI treatment often suffer from Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness in hands, fingers, knees, hips and feet, which may limit treatment and subsequently increase BC mortality. The depletion of estrogen following AI initiation has been postulated to cause AIMSS. However, it has not yet been fully established about the clinical significance of AIMSS and its risk factors and the underlying mechanisms. The aim of this study is to identify epidemiologic risk factors associated with the development of AIMSS in BC patients on adjuvant AI therapy. Methods: We conducted a retrospective review of medical records among 111 stages 0-III hormone receptor positive BC patients who received adjuvant AI therapy, including anastrozole, letrozole or exemestane, between January 2009 and June 2017, at the University of Maryland Greenebaum Comprehensive Cancer Center. To be eligible, women had to be either postmenopausal or premenopausal, on a GnRH analog for at least 3 months, and report of no AIMSS before the AI initiation. We collected patients’ data on demographics, lifestyle factors, reproductive histories, tumor characteristics, types of AI and cancer treatment, co-morbidities, use of medications, length of AI therapy, and onset and severity of AIMSS. We defined severe AIMSS as AIMSS requiring the change of AI therapy or discontinuation of AI. The demographics and clinicopathological characteristics of patients on AI therapy and frequencies of AIMSS onset during AI treatment was characterized with means (SDs) or percentages. To estimate the association of severe AIMSS with epidemiologic risk factors, odds ratios (ORs) and 95% confidence intervals were calculated using multivariable-adjusted logistic regression. Results: This study included 111 BC patients with a mean age of 64 years. Their mean BMI at time of BC diagnosis was 30.8 kg/m2, and 41% of patients were White, 39% were Black, 4% were Asian/Pacific Islander, and 16% were other. Majority of patients (77%) had no prior experience of tamoxifen use and used letrozole as an initial AI therapy (70.3%); 15.3% used anastrozole, and 14.4% used exemestane. We found that 52.6% of patients experienced any degree of AIMSS while on AI therapy. In particular, 19.8% of patients required change or holding AI therapy, and 3.6% permanently discontinued AI because of AIMSS. We observed that older age at AI therapy initiation and higher levels of circulating vitamin D-25OH were significantly associated with lower odds of severe AIMSS. Multivariate ORs (95% Cis) comparing the highest to the lowest tertile of age and vitamin D levels at AI initiation were 0.18 (0.05-0.71) and 0.10 (0.02-0.49), respectively (all P-trend: ≤ 0.04). There were no significant association between race, body mass index, smoking, alcohol use, reproductive factors, type of AI therapy, and tamoxifen use prior to AI therapy. Conclusions: In our study, nearly 52.6% of BC patients on adjuvant AI therapy experienced AIMSS. Of those, 23.4% changed or discontinued AI regimen due to severe AIMSS. Older age and higher circulating levels of vitamin D-25OH at the initiation of adjuvant AI therapy were associated with lower risk of developing severe AIMSS. The study results support the clinical significance of AIMSS in BC patients leading to decreased adherence to AI therapy. The replication of our association with age and vitamin D levels in a larger study is warranted as it may provide a greater insight into etiologies of AIMSS. Citation Format: Yamin Sun, Simran Elder, Seungyoun Jung, Candace Mainor, Shruti Murali, Paula Rosenblatt, Katherine Tkaczuk. Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-13.

Chinese Medicine Yishen Jiangu Granules () on Aromatase Inhibitor-Associated Musculoskeletal Symptoms.

To assess the effectiveness of Yishen Jiangu Granules (, YSJGG) on aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). A single-arm, open-label study was conducted in 34 postmenopausal women with breast cancer who experienced AIMSS. Patients were treated with YSJGG for 12 weeks (12.4 g orally twice daily). The primary outcome was a change in the mean worst pain score of Brief Pain Inventory-Short Form (BPI-SF) over 12 weeks, and the second outcomes included changes in pain severity and pain-related interference of BPI-SF and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH), the Functional Assessment of Cancer Therapy-Breast (FACT-B), bone mineral density (BMD) and blood indices such as calcium (Ca), phosphate (P), and alkaline phosphatase (ALP). Of 37 women recruited, 30 initiated the therapy and 24 were evaluable at 12 weeks. The primary outcome (BPI-SF worst pain scores) achieved a 2.17-point reduction compared with baseline (5.75±1.87 vs 3.58±2.15, P<0.01). There were reductions in pain severity (decreased 1.65, P<0.01) and pain-related interference (decreased 2.55, P<0.01). The changes in WOMAC and M-SACRAH scores were similar to BPI-SF (P<0.05). In the FACT-B, only physical well-being and functional well-being were improved compared with baseline (P<0.05). No clinical differences were found in BMD, Ca, P and ALP. YSJGG is an effective and well-tolerated agent to reduce AIMSS.

Effects of the Chinese medicine Yi Shen Jian Gu granules on aromatase inhibitor-associated musculoskeletal symptoms: A randomized, controlled clinical trial

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are prevalent among patients on AI therapy, which leads to a lower quality of life and poor adherence to AI treatment. We evaluated whether Yi Shen Jian Gu granules (YSJG) is effective and safe to relieve AIMSS in patients with breast cancer.Eligible participants were randomly assigned to the YSJG group or the placebo group. Both groups had a 12-week treatment period and a 12-week follow-up period. Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) were obtained at baseline and at 4, 8, 12 and 24 weeks.Of 146 participants enrolled, 84 were randomly assigned, and 77 were evaluable at 12 weeks. Baseline characteristics were comparable between two groups. The primary outcome was the differences in mean BPI-SF scores at 12 weeks. The worst pain scores decreased by 3.10 points (50.2%; 95% CI, 2.50 to 3.65) for YSJG group compared with a 1.63-point decrease (26.9%; 95% CI, 3.86 to 4.97) for the placebo group (P = 0.001). Significantly improvements were also observed for the WOMAC and M-SACRAH. Possibly YSJG-related side effects were grade 1 nausea (10%) and grade 2 diarrhea (2%). Serum follicle-stimulating hormone and serum estradiol were kept in the postmenopausal range before and after YSJG treatment.Patients with AIMSS treated with YSJG granules had significant improvements in musculoskeletal symptoms. YSJG is effective, safe and well-tolerated in managing AIMSS. Trial registrationISCTN: ISRCTN06129599 (assigned 14 August 2013).

Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial.

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) frequently occur in women being treated for breast cancer. Prior studies suggest high prevalence of vitamin D deficiency in breast cancer patients with musculoskeletal (MS) pain. We conducted a randomized, placebo-controlled trial to determine if 30,000IU vitamin D3 per week (VitD3) would prevent worsening of AIMSS in women starting adjuvant letrozole for breast cancer. Women with stage I-III breast cancer starting adjuvant letrozole and 25(OH)D level ≤40ng/ml were eligible. All subjects received standard daily supplement of 1200mg calcium and 600IU vitamin D3 and were randomized to 30,000IU oral VitD3/week or placebo. Pain, disability, fatigue, quality of life, 25(OH)D levels, and hand grip strength were assessed at baseline, 12, and 24weeks. The primary endpoint was incidence of an AIMSS event. Median age of the 160 subjects (80/arm) was 61. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12weeks, and 31 at 24weeks in the placebo arm and 22, 53, and 57 in the VitD3 arm. There were no serious adverse events. At week 24, 51% of women assigned to placebo had a protocol defined AIMSS event (worsening of joint pain using a categorical pain intensity scale (CPIS), disability from joint pain using HAQ-II, or discontinuation of letrozole due to MS symptoms) vs. 37% of women assigned to VitD3 (p=0.069). When the brief pain inventory (BPI) was used instead of CPIS, the difference was statistically significant: 56 vs. 39% (p=0.024). Although 30,000IU/week of oral vitamin D3 is safe and effective in achieving adequate vitamin D levels, it was not associated with a decrease in AIMSS events based on the primary endpoint. Post-hoc analysis using a different tool suggests potential benefit of vitamin D3 in reducing AIMSS.

Erratum: Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

Erratum: Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

Management of aromatase inhibitor-associated musculoskeletal symptoms: A systematic review.

157 Background: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are experienced by a significant number of women on adjuvant aromatase inhibitors for breast cancer. These symptoms can result in therapy noncompliance and there is no accepted standardised treatment. We believe that this is the first systematic review to consider the evidence for all pharmacological and non-pharmacological interventions in the treatment of AIMSS. Methods: We conducted a systematic search in PubMed, EMBASE, CINAHL and CENTRAL. Clinical trials and observational studies for all potential pharmacological and non-pharmacological interventions were included. Two reviewers screened the results and extracted the relevant data. Risk of bias for the full papers were assessed using JADAD or a modified Newcastle Ottawa score, with conference abstracts and letters to the editor excluded from this process. Results: Of 1260 records being identified, 887 unique citations were screened with 93 full text papers retrieved for assessment, and 37 selected for inclusion. We identified 9 pharmacological interventions (RCT = 3, pre-post = 4, cohort = 2) and 28 non-pharmacological interventions (RCT/CCT = 16, pre-post = 8, cohort = 3). The largest number of studies were for various exercise interventions (n = 7) with the largest trial showing a 29% decrease in worst joint pain scores compared to the control (2%, p &lt; 0.001). The highest number of RCTs was for acupuncture (n = 5), the majority of which showed a significant benefit with both real and sham acupuncture. Other single RCTs showing benefit include the use of testosterone, calcitonin and etoricoxib. No study adequately controlled for contamination bias from extraneous variables of both pharmacological and non-pharmacological interventions. Conclusions: Given that pharmacological treatment is often recommended for AIMSS, it is surprising that there is limited published evidence for its use. Although the interventions being used appear tolerable with minimal adverse effects, the current level of evidence is low, and additional large RCTs with more rigorous controlling for contamination from other interventions are required to confirm some of the reported promising results.

Issues associated with Aromatase Inhibitor–Associated Musculoskeletal Symptoms in Breast Cancer

Issues associated with Aromatase Inhibitor–Associated Musculoskeletal Symptoms in Breast Cancer

A randomized trial of vitamin D3 in aromatase inhibitor-associated musculoskeletal symptoms.

9608 Background: Vitamin D3 supplementation (D3) has been suggested as a treatment for aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS), but efficacy and safety are unclear. Met...

A phase II study evaluating efficacy of zoledronic acid in prevention of aromatase inhibitor (AI)-associated musculoskeletal symptoms: The ZAP trial.

9615 Background: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) contribute to significant morbidity and therapy discontinuation. Retrospective data suggest that bisphosphonates may...

Effects of the traditional Chinese medicine Yi Shen Jian Gu granules on aromatase inhibitor-associated musculoskeletal symptoms: a study protocol for a multicenter, randomized, controlled clinical trial.

BackgroundAromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. One of the main adverse effects of AIs is musculoskeletal symptoms, which leads to a lower quality of life and poor adherence to AI treatment. To date, no effective management of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) has been developed.Methods/designTo determine whether the traditional Chinese medicine Yi Shen Jian Gu granules could effectively manage AIMSS we will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients experiencing musculoskeletal symptoms after taking AIs will be enrolled and treated with traditional Chinese medicine or placebo for 12 weeks. The primary outcome measures include Brief Pain Inventory-Short Form, Western Ontario and McMaster Universities Osteoarthritis Index, and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands, which will be obtained at baseline and at 4, 8, 12 and 24 weeks.DiscussionThe results of this study will provide a new strategy to help relieve AIMSS.Trial registrationISCTN: ISRCTN06129599 (assigned 14 August 2013).

Aromatase Inhibitor Associated Musculoskeletal Symptoms are associated with Reduced Physical Activity among Breast Cancer Survivors

Physical activity (PA) has numerous health benefits for breast cancer survivors. Recent data suggest that some breast cancer survivors treated with aromatase inhibitors may experience aromatase inhibitor associated musculoskeletal symptoms. It is unknown whether aromatase inhibitor associated musculoskeletal symptoms are associated with reduced PA and what other risk factors are associated with such PA reductions. We conducted a cross-sectional study at a large university-based breast cancer clinic among breast cancer survivors prescribed an aromatase inhibitor. At routine follow-up, we surveyed participants about aromatase inhibitor associated musculoskeletal symptoms, as well as pre-aromatase inhibitor, and current, PA levels. Among 300 participants, 90 (30%) reported a reduction of PA since the initiation of aromatase inhibitor therapy. Those with aromatase inhibitor associated musculoskeletal symptoms were more likely to report decreased PA (62% versus 38%, p = 0.001) compared with those without aromatase inhibitor associated musculoskeletal symptoms. In multivariate analyses, aromatase inhibitor associated musculoskeletal symptoms (odds ratio [OR] = 2.29 [95% confidence interval [CI]: 1.36-3.86]), and body mass index (OR = 1.06 [95% CI: 1.02-1.12]) were associated with reductions in PA. In subgroup analysis among breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms, self-reported lower extremity joint pain (OR = 1.23 [95% CI: 1.00-1.50]) and impaired lower extremity physical function (OR = 1.07 [95% CI: 1.01-1.14]) were associated with reductions in PA. Breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms were more likely to report reductions in PA since initiating aromatase inhibitor therapy compared with those without aromatase inhibitor associated musculoskeletal symptoms. Our findings suggest that tailored interventions targeting lower extremity functional limitations are needed to enable breast cancer survivors with aromatase inhibitor associated musculoskeletal symptoms to participate in PA.

Aromatase inhibitor-associated musculoskeletal symptoms: incidence and associated factors

PurposeArthralgia is the most common side effect in breast cancer patients receiving aromatase inhibitor (AI) therapy. Few studies have evaluated the risk factors, onset, and incidence of musculoskeletal pain in these patients. This study identifies the risk factors of AI-related severe arthralgia and their prevalence.MethodsAll the clinical and pathological records of postmenopausal patients diagnosed with invasive breast cancer using AI at Samsung Medical Center from January 2005 to November 2007 were reviewed. Multivariate logistic regression analyses were performed to evaluate the risk factors of AI-associated musculoskeletal symptoms (AIMSS) and factors associated with AI discontinuance.ResultsAmong 299 patients, 69 patients (23%) experienced musculoskeletal symptoms attributed to AI use. In multivariate logistic regression analysis, no statistically significant outcome was found to confirm the risk factors for the development of AIMSS. Among the 69 patients who experienced AI-associated musculoskeletal symptoms, 29 (39.7%) discontinued AI use. Multivariate logistic regression analyses revealed an association of prior tamoxifen use with discontinuance of AI (P < 0.01; odds ratio, 4.27; 95% confidence interval, 1.74 to 10.50).ConclusionPrior use of tamoxifen is related to discontinuation of AI due to AI-associated severe arthralgia. Special monitoring and proper pain control for these patients should be considered during the treatment period.