Summary of main results

This Cochrane Review investigated systemic therapies for the prevention and treatment of AIMSS in early breast cancer, and included 17 RCTs with 2034 randomised participants. Systemic therapies investigated were diverse and included 'conventional' pharmacological therapies and CAM, and also included studies of vitamin D in the setting of insufficiency. There was limited information about certain study interventions or placebo ingredients (or both). In most studies, the comparator arm was a placebo, however, in some studies, the comparator was a vitamin supplement. Meta‐analysis was limited in this review. Due to the clinical and methodological heterogeneity of the studies and the insufficient data available from several studies, only one outcome had data that could be combined for meta‐analysis. Overall, the certainty of the evidence was very low for multiple outcomes for systemic therapies assessing prevention and treatment of AIMSS.

For preventing AIMSS, we found that the evidence for the effect of systemic therapies on change in pain from baseline to the end of the intervention was very uncertain. The evidence suggests systemic therapies for preventing AIMSS may have little to no effect on grip strength, little to no effect on change in HRQoL and BCS‐QoL from baseline to the end of the intervention, and little to no effect on women continuing to take their AI, although the certainty of this evidence was low. The evidence was very uncertain on the outcome of change in incidence of AIMSS. The evidence is very uncertain for the safety of systemic therapies for the prevention of AIMSS. One study of a COX‐2 inhibitor had an FDA safety alert issued for this class of medications during the study leading to significant participant withdrawal/discontinuation; however, there were no serious adverse events in this study, or any other prevention study. There were no data to assess the impact of systemic therapies for prevention of AIMSS on stiffness, BCSS or OS from the prevention studies.

For treating AIMSS, the evidence was very uncertain about the effect of systemic therapies on the effect of change in pain, stiffness, HRQoL and BCS‐QoL from baseline to the end of the intervention. The evidence suggests systemic therapies may have little to no effect on grip strength, although the certainty of this evidence was low. The evidence is very uncertain about the safety data for the use of systemic therapies for the treatment of AIMSS. There were no grade four or five adverse events in any of the treatment studies. One study reported significantly more all‐grade adverse events with duloxetine than with control (78% with duloxetine versus 50% with control; P < 0.001). There were no data on the incidence of AIMSS, number of women continuing to take AI, or BCS‐QoL or OS from the treatment studies. 

The follow‐up interval was relatively short for most studies, and hence long‐term safety data are not available. Safety results should thus be interpreted with caution for both prevention and treatment studies.

Overall completeness and applicability of evidence

This review included 17 trials on 2034 participants. Insufficient data was a difficulty in this review, although additional data/information was obtained by author correspondence for four studies (Chan 2017; Khan 2017; Niravath 2019; Sordi 2019). The studies in this review were diverse in terms of clinical and methodological heterogeneity. There is considerable heterogeneity in the type of systemic therapy studied. These included 'conventional' pharmacological therapies and CAM, with the vitamin D studies not all fitting the Cochrane definition of CAM (Wieland 2011). There was also heterogeneity in the route of administration of the studied systemic therapy with most being oral therapy (16 trials) and only one trial of topical therapy with possible or postulated systemic absorption and effects (Chan 2017); the proposed mechanism of action of the systemic therapy; and the duration of intervention and the follow‐up. Several studies had limited details about the intervention, including the active compounds or the comparator arms (or both) (YSJG granules (Peng 2018), bionic tiger bone (Li 2017), Blue Citrus (Massimino 2011), tart cherry (Shenouda 2019), Cat's claw (Sordi 2019)). There were no known systemic interventions investigating the treatment of AIMSS missed in this review, but given the limited information from some studies and the incomplete understanding of the aetiology of AIMSS (Hershman 2015b; Niravath 2013), it is, therefore, not possible to make definitive conclusions about whether all relevant systemic or potentially effective therapy studies have been completed. We identified no studies that required translation into English, which raises the possibility that this review may have missed potential studies investigating a complementary or alternative medicine reported in a language other than English. Although non‐English papers were not excluded in this review, we searched only Western databases. There are ongoing studies of other systemic therapies with differing proposed mechanisms of action (see Characteristics of ongoing studies table). This review only included the investigation of systemic therapies for the treatment of AIMSS and, therefore, excluded other interventions that have been trialled for AIMSS that were not considered to be a systemic therapy, such as acupuncture and exercise. Most studies included in this analysis were conducted in hospital/oncology outpatient clinic settings. The limited information provided by some studies may limit the applicability to certain clinical settings.

The studies of vitamin D were methodologically and clinically heterogeneous (Khan 2017; Niravath 2019; Rastelli 2011; Shapiro 2016), and were performed either to prevent or treat AIMSS. Inclusion criteria in two of the vitamin D studies required participants to have specific 25‐OHD levels at baseline (Khan 2017; Rastelli 2011), particularly 25‐OHD levels of 40 ng/mL or less for the prevention trial of Khan 2017 and between 10 ng/mL and 29 ng/mL for the treatment trial of Rastelli 2011. Vitamin D deficiency is defined by most experts as a serum 25‐OHD level less than 20 ng/mL, and relative insufficiency of vitamin D as a level of 25‐OHD of 21 ng/mL to 29 ng/mL (Holick 2007). All women included in Rastelli 2011 had vitamin D deficiency or insufficiency, and many women in Khan 2017 also met these criteria. "Vitamin D deficiency in adults can precipitate or exacerbate osteopenia and osteoporosis, cause osteomalacia and muscle weakness, and increase the risk of fracture" (Holick 2007) and pain associated with these conditions could potentially be confused with AIMSS. Both studies were performed in the USA in predominantly white women (Khan 2017; Rastelli 2011). A nested case‐control correlative study has suggested vitamin D levels were not significantly associated with development of AI arthralgia (Niravath 2018). The studies that selected women with inclusion criteria related to serum vitamin D levels may therefore have uncertain generalisability and applicability to the entire population of women with AIMSS, and limit the overall completeness of the evidence related to vitamin D.

Patient populations included in this review had ethnic and racial diversity; however, diversity was sometimes related to particular characteristics of certain studied systemic therapy interventions, notably CAM, and to the ethnic, racial and cultural characteristics of the study populations (e.g. studies of TCM conducted in China) (Peng 2018; Li 2017); study of traditional Incan medicine, Cat's claw, conducted in Brazil (Sordi 2019). However, this was not consistent across all studies (e.g. study of TCM Blue Citrus conducted in the USA) (Massimino 2011). For studies examining TCM, choice of this intervention for AIMSS research in Chinese populations may relate to beliefs that TCMs for cancer care based on "deep cultural grounding", and beliefs that TCM is safe and effective (Xu 2006). Chinese herbal medicine was used by 76.8% (Chen 2008) and 86.7 % (Cui 2004) of Chinese women with breast cancer surveyed in Shanghai. In contrast, in a Canadian survey, although more than 80% of women with breast cancer reported using CAM (41% specifically to manage their breast cancer), only 2.2% of women with breast cancer consulted a TCM practitioner (Boon 2007). CAM use in ethnically and racially diverse populations has been found to be complex and nuanced; however, ethnicity has an independent role in the type of CAM used (Kronenberg 2006). One systematic review has highlighted the importance of traditional and CAM to indigenous people with cancer of Australia, Canada, New Zealand and the USA (Gall 2018). Ethnic, racial, cultural and linguistic diversity may therefore have relevance in limiting applicability, acceptability and generalisability of certain studied systemic therapy interventions (particularly traditional medicines and CAM) to other diverse populations with diverse cultural belief systems and corresponding traditional and CAM preferences. In addition, certain ethnic and racial groups were not adequately represented (or represented at all) in other studies of certain systemic therapies. As examples, in the treatment studies by Henry 2018 of duloxetine, Hershman 2015a of O3FA, Khan 2017 and Rastelli 2011 of vitamin D, greater than 85% of participants were white. However, in the prevention study of vitamin D by Niravath 2019 conducted in the USA, most participants enrolled were from minorities with 44% Latina people and 18% African American people enrolled.

The incidence of AIMSS has generally been reported to be approximately 50% (Beckwee 2017; Crew 2007; Henry 2008); however, one Chinese cohort reported an incidence of 72% (Xu 2014). A degree of current uncertainty about racial and ethnic variability in the incidence of AIMSS may affect data applicability and generalisability from this review. One placebo‐controlled trial of letrozole after five years of tamoxifen demonstrated in an unplanned subgroup analysis that women from minority ethnic and racial groups receiving letrozole had less arthritis however compliance was poorer than in Caucasian women receiving letrozole, and highlighted the low number of minority participants enrolled in this trial (Moy 2006). Pharmacogenetic predictors of AI toxicity have been reported but have not been adequately validated (Hertz 2017). Therefore, there is insufficient evidence from this review about differences in adverse events and other outcomes with the clinically heterogeneous systemic therapy interventions studied between different ethnic and racial participant groups and this may also limit generalisability and applicability.

The median age of women diagnosed with breast cancer in the USA is 62 years (Howlader 2019), similar to this review, and also similar to postmenopausal women diagnosed with breast cancer in other high‐income countries. However, similar to the Cochrane Review "Exercise therapies for preventing or treating aromatase inhibitor‐induced musculoskeletal symptoms in early breast cancer"(Roberts 2020), very few postmenopausal women older (greater than 75 years) or younger (less than 35 years) were included. Younger women at higher risk of recurrence are increasingly being treated with AI in combination with ovarian function suppression rather than with tamoxifen alone, due to improvements in DFS reported by landmark trials (Francis 2015; Francis 2018). There were high rates of musculoskeletal symptoms reported in these trials (88.7% for ovarian suppression with exemestane treatment versus 69% with tamoxifen treatment alone). The studies in this review included very few young women rendered postmenopausal and treated with AI, likely as a result of when the landmark trials were published (Francis 2015; Francis 2018). Young women treated with AI and ovarian function suppression or ablation represent an area of unmet clinical need, and an increasing population with AIMSS whose baseline incidence may be different to women included in this review. AIMSS may be inversely correlated with time since menopause (Mao 2009), and younger women with abrupt oestrogen withdrawal may be at higher risk of symptoms. Systemic therapy interventions for AIMSS may therefore have different applicability or even effectiveness in younger women.

Data were available for the primary outcome of pain for many of the studies. However, unfortunately data for certain important missing outcomes was unable to be obtained (e.g. Birrell 2009) to allow meta‐analysis (e.g. for testosterone in treatment – Birrell 2009; Cathcart‐Rake 2020). Many studies did not assess BCS‐QoL or HRQoL outcomes. Women experiencing pain from taking AI experience changes in QoL, with the degree of change in QoL depending on the type of pain experienced (Laroche 2017). The minimal QoL evidence available for this review raises concerns with completeness of the evidence. Many studies did not report important AIMSS PROs such as joint stiffness. There was no evidence available on the effect of systemic therapies for treatment of AIMSS on the incidence of AIMSS. There was no evidence available on the effect of systemic therapies for AIMSS on OS. 

Studies that included participants with AIMSS at baseline varied in their definitions of AIMSS, and the comorbid conditions included. As noted in the Cochrane Review "Exercise therapies for preventing or treating aromatase inhibitor‐induced musculoskeletal symptoms in early breast cancer" (Roberts 2020), the lack of consensus on standardised definitions for AIMSS, the absence of objective outcome measures, and the multiple PROs reported in different studies meant it was not possible to make conclusions on completeness of the evidence of outcome measures in this review. These research barriers have been noted previously by Hershman 2015b and Niravath 2013. As the trials assessed multiple varied outcomes, and interventions were heterogeneous, it was neither possible nor appropriate to combine the majority of the outcomes for meta‐analysis. Long‐term safety data were lacking for many of the studies. Due to small sample sizes and heterogeneity of the trials, planned subgroup analysis was not possible, which further limits applicability of the findings.

There was considerable heterogeneity in the timing of the outcome measures of the included trials, which also limited comparability. The duration of the intervention in the included trials ranged between four weeks and two years. AIMSS are chronic symptoms with an unpredictable course. There was also considerable heterogeneity in follow‐up in the included studies. Evidence for long‐term benefits and harms is of increasing importance given the guideline recommendations for extended duration of AI therapy in certain women with breast cancer (Burstein 2019); however, limited evidence was available from this review in this setting. Two of the prevention studies reported adherence rates to AI therapy (Khan 2017; Niravath 2019), and in none of the treatment studies. Adherence to AI therapy is an important outcome of an intervention for AIMSS, as AI adherence impacts breast cancer survival (Chirgwin 2016). Therefore, evidence is incomplete given the very low‐certainty evidence from the small number of studies reporting AI adherence as an outcome.

There were notable limitations in the data obtained from this review. Many studies were of small size and either had some concerns or were at high risk of bias, and evidence was of very low certainty across multiple outcomes. As a result, caution needs to be taken in the interpretation of the outcome data from this review, and in assessment of the long‐term risks and harms of systemic therapies for AIMSS. These considerations also limit the generalisability and applicability of the studied systemic therapy interventions.

The outcomes analysed in this review were chosen based on which outcome domains the studies researching AIMSS used at the time of our protocol development, in addition to guidance from working groups such as Outcome Measures in Rheumatology (OMERACT 2021). In updates of this review, we would consider utilising Cochrane Musculoskeletal Group's core outcome list (CMSG 2021), although outcomes would have to extrapolated from other predefined musculoskeletal conditions, such as osteoarthritis or rheumatoid arthritis. 

Quality of the evidence

Very low‐certainty evidence does not support the use of systemic therapy to prevent or treat AIMSS. Studies were generally of small size with the number of participants ranging from 37 to 299. Clinically heterogeneous systemic therapies or the clinically heterogenous settings in which they were studied (or both) meant that it was not appropriate to combine most outcomes for meta‐analysis. Hence, outcome assessments had low numbers of participants included, which led to downgrading of the evidence due to concerns with imprecision. 

Many studies were either at moderate risk of bias, or had some concerns. A few of the studies were not blinded. One study had higher rates of adverse events with the intervention (duloxetine) than with the placebo, leading to higher numbers of participants successfully guessing which intervention they were receiving, and potentially unblinding these participants (Henry 2018). Similarly, another study used an intervention dosed three times daily versus a comparator with single daily dosing, which posed a high risk of unblinding the participants and assessors in this 'double‐blinded' trial (Li 2017). For these studies, there was a high risk of performance bias. There was also a high risk of detection bias as most outcomes were PROs, and the remaining outcomes were not blinded to outcome assessors. Several of the studies had inadequate outcome data and selective reporting of outcomes. There was high risk of attrition bias in several studies, which had a high risk of affecting outcome data, particularly in such small studies. We downgraded the evidence by at least one level for all our outcomes related to these studies due to serious concerns with the risk of bias. 

Several studies had restrictive entry criteria which meant that the evidence obtained may not directly answer our review question. Particularly several of the vitamin D studies had criteria that specified low vitamin D levels for enrolment, specifically 25‐OHD levels at baseline (Khan 2017; Rastelli 2011), particularly 25‐OHD levels of 40 ng/mL or less for Khan 2017 and between 10 ng/mL and 29 ng/mL for Rastelli 2011. We downgraded the evidence by at least one level for all of our outcomes related to these studies due to indirectness, as these studies investigated a patient population that is not representative of all people with AIMSS. A number of outcomes were also downgraded for indirectness due to studies including patient populations that were not well‐defined for AIMSS. For example, one study included people experiencing musculoskeletal symptoms regardless of temporal association with the start of the AI, which resulted in a patient population that may have had pre‐existing musculoskeletal conditions rather than AIMSS.

There was no statistical heterogeneity in the single meta‐analysis performed in this review. However, there was significant clinical heterogeneity between interventions investigated in the review, which resulted in downgrading of the evidence for inconsistency for outcomes that incorporated multiple clinically heterogeneous interventions. 

Four of the 17 studies have been published only in abstract form (Birrell 2009; Massimino 2011; Rosati 2011; Shenouda 2019). A considerable period of time has elapsed since the publication of three of these studies (Birrell 2009; Massimino 2011; Rosati 2011), and we were unable to obtain data. Some of these outcomes were of significant interest to this review; however, these were unable to be obtained. One study of etoricoxib had an FDA safety alert issued for the class of drug (COX‐2 inhibitors) during the study leading to high rates of participant withdrawal (Rosati 2011). Missing outcomes raise concerns about the overall quality of the evidence, and the potential for influence of publication bias on our outcomes. The only outcome with enough studies to warrant investigation with a funnel plot for evidence of publication bias confirmed our suspicions of the presence of publication bias. Concerns around publication bias led to downgrading of the evidence by one level.

Potential biases in the review process

This review undertook a comprehensive search strategy led by an Information Specialist (KR), with no language limitation. This is a strength of this review. Several authors (KER, SC, IA and NW) independently screened reference lists of all included studies and any systematic reviews (two authors for all references). We handsearched conference and meeting abstracts for the relevant organisations. Two review authors (IA, SC, KER, NW) independently performed data extraction and risk of bias assessments on each study. The search strategy should have identified most studies, however all studies identified were published in English language journals. Although several studies were conducted in non‐English speaking countries (e.g. China (Li 2017; Liu 2014; Peng 2018) and Brazil (Sordi 2019)), and were published in English, this observation does raise the possibility of a potential bias of missed publications in languages other than English.

The inconsistent definition of AIMSS (Hershman 2015b; Niravath 2013), and the potentially wide definition of systemic therapies may have been potential sources of bias in the search strategy. A wide search strategy was employed to attempt to account for these potential biases. All potential generally accepted definitions of systemic therapies were included in the search strategy, as were all AI in current clinical practice.

We contacted 15 study authors for further information. We received replies from four authors. A limitation of this review is that certain data were unavailable, which introduced selection bias. Certain outcomes were not available for meta‐analysis, due to our inability to obtain further data on request.

We did not systematically evaluate the measurement instruments for AIMSS in this review due to resource constraints. This is a potential limitation of our review; however, there is significant variability in the outcome assessments for AIMSS and no consensus (Hershman 2015b; Niravath 2013). Assessment of outcome measurements would therefore need to be interpreted within this clinical and research heterogeneity.

Agreements and disagreements with other studies or reviews

This Cochrane Review is the first of systemic therapies for prevention or treatment of AIMSS in postmenopausal women with early breast cancer. We searched other studies and reviews (systematic reviews and meta‐analyses) for comparison with this review. A broad search strategy identified the references, and we handsearched the identified studies for systematic reviews and meta‐analyses on the research question. The same reviews for treatment of AIMSS (which included systemic therapies and exercise) (Kim 2018; Nahm 2018; Roberts 2017; Yang 2017) were also identified by several of the current authorship team involved in a previous Cochrane Review of exercise for the prevention and management of AIMSS in early breast cancer (Roberts 2020), albeit the search date was earlier. One systematic review of systematic reviews (Kim 2018) identified the same three systematic reviews that included systemic therapies (Nahm 2018; Roberts 2017; Yang 2017). We excluded systematic reviews of acupuncture alone for AIMSS.

Roberts 2017 published a review entitled "Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early breast cancer: a systematic review and meta‐analysis". Several of the authors from the current Cochrane Review were also involved in this review. The author's search strategy was designed to include both prospective and retrospective clinical trials, including RCTs, cohort and case‐control studies and preventive trials of interventions for AIMSS including pharmacological, non‐pharmacological (including exercise), and CAM interventions. Meta‐analysis was conducted when there were sufficient data. Publications in English language only were considered. Studies of systemic therapy were grouped narratively into pharmacological therapies and CAM, and AIMSS outcomes reported. In contrast to our review, no meta‐analysis of any AIMSS outcomes was undertaken for systemic therapies. There was significant between‐study heterogeneity. Non‐randomised data was included in the overall systematic review of Roberts 2017 and the scope of studies included was broader, and hence this review is not directly comparable to our current Cochrane Review. In agreement with our review, evidence quality was determined to be poor overall, and there was limited evidence found to recommend systemic therapies for management of AIMSS. In contrast to our current Cochrane Review, Roberts 2017 undertook no reporting or analysis of stiffness, QoL outcomes or adverse event reporting.

The review by Yang 2017 entitled "Interventions for the treatment of aromatase inhibitor associated arthralgia in breast cancer survivors. A systematic review and meta‐analysis" included all studies that were RCTs and "quasi‐experimental design". The primary outcome was pain mean score as assessed by BPI at the end time point of the intervention. Yang 2017 separated the studies into "pharmacological approaches" and "nutritional supplementation". Four non‐randomised studies were said to be included in pharmacological approaches in the meta‐analysis (Briot 2010; Henry 2011; Kubo 2012; Zhang 2010), with pharmacological approaches reported to show "a very large effect in improving pain" (SMD −1.186, 95% CI −2.312 to −0.060). This subgroup meta‐analysis, with the inclusion of non‐randomised data, is different to our Cochrane Review. Three studies of diverse nutritional supplements were included together in meta‐analysis including a single‐arm non‐randomised open‐label phase two trial of glucosamine with chondroitin (Greenlee 2013), and RCTs of O3‐FA (Hershman 2015a) and vitamin D (Rastelli 2011). Nutritional supplementation showed no significant effect on joint pain, although there was "a tendency to decrease joint pain" (SMD −0.124, 95% CI −0.341 to 0.092). The review by Yang 2017 differs from our Cochrane Review as we have not analysed such diverse systemic therapies together due their postulated differing mechanisms of action, and we have not included non‐randomised data. In addition, in contrast to our current Cochrane Review, Yang 2017 did not undertake adverse event reporting.

In contrast to our current review, the systematic review by Nahm 2018 performed no meta‐analyses. This systematic review is not directly comparable to our current Cochrane Review as Nahm 2018 included all management interventions for AIMSS, and included non‐ randomised studies. In agreement with our review, the authors concluded, "While several trials had positive findings, the major methodological limitations of the studies meant that no definitive evidence could be found supporting any of the interventions".

Kim 2018 performed the most recent review with a search date of June 2018. Kim 2018 systematically reviewed all eligible systematic reviews and then subjected these to evidence mapping. The RCTs included in the reviews were handsearched for network meta‐analysis. The search strategy, statistical methodology and included studies therefore are different to our current Cochrane Review. Mean and SD of BPI was the outcome measure. Kim 2018 identified six trials that provided information on BPI for inclusion in their network meta‐analysis. Two of the six RCT included in the network meta‐analysis were systemic therapy studies, which were an RCT of O3‐FA (Lustberg 2018), and vitamin D (Rastelli 2011). These RCTs were not combined but compared separately to wait list control. Kim 2018 concluded "omega‐3 fatty acids (MD −2.10, 95% CI −3.23 to −0.97) showed statistically significant improvement in pain severity scores". However, a larger RCT of O3‐FA by Hershman 2015a of 262 participants which had BPI‐SF as a primary endpoint was not included in this network meta‐analysis, which is in contrast to our current Cochrane Review which included Hershman 2015a. For network meta‐analysis, the authors concluded "all interventions had a better effect than vitamin D" with only the trial by Rastelli 2011 included in their network meta‐analysis. The review by Kim 2018 is not comparable to our Cochrane Review as in contrast to our current review, it did not include vitamin D studies by Khan 2017, Shapiro 2016 (did not use BPI as an endpoint) and Niravath 2019 (published subsequently). The conclusions of Kim 2018 are not in agreement with our Cochrane Review findings. Adverse event reporting was concluded to be poor, and as a result of this, Kim 2018 did not perform network meta‐analysis of adverse events. We found that adverse event reporting was overall of very low‐certainty evidence, and data were not available from certain studies.