This study found an association between muscle strength and fracture risk in women with breast cancer. Most of the women investigated showed preserved sarcopenia phenotypes and a low risk of fractures. In contrast, most of the group was characterized by excess body fat.
The relationship between sarcopenia phenotypes and bone health is described in the literature. It does, however, remain unexplored in women with breast cancer. Most previous studies have determined fracture risk through fracture incidence in the population evaluated, and there are few studies using FRAX as an assessment tool [19, 20, 38].
We observed that patients with higher fracture risk had lower HGS. Previous studies demonstrate that low HGS is an independent risk factor for fragility fractures and that fractured patients have relatively low HGS [39, 40].
Amarowicz et al.  evaluated postmenopausal women with vertebral fractures and observed that patients in the reduced HGS group had more fractures. Thus, muscle strength was considered a potential parameter for use in clinical practice to identify patients at risk for vertebral fractures . Denk et al.  performed a systematic review on the association between reduced HGS and hip fracture in the elderly and observed that low HGS was associated with an increased risk of fracture in all studies analyzed.
This indicator is related not only to the risk and incidence of fractures, but also to the recovery of fractured individuals . Patients with higher HGS show better recovery after hip fracture, which suggests that it can be used as a screening tool to identify those who need intensive rehabilitation [42,43,44]. Such a finding may contribute to the prognosis of these patients, since hip fractures are most serious and cause permanent disability in approximately 20% of survivors, with only about 40% of the afflicted individuals eventually attaining pre-injury function levels .
The relationship between reduced HGS and increased fracture risk can be explained by the association between low muscle strength and decreased BMD . The mechanical stress of muscle contraction can contribute to the maintenance of bone mass, as it exerts trophic and adaptive effects. Since HGS is a representative measure of muscle strength in the body, reduced values may indicate not only an increased risk of falling but also a reduction in local muscle strength, which is associated with the occurrence of fractures . In this context, positive associations between back muscle strength and lumbar spine BMD have been reported, as well as an increased risk of vertebral fractures in situations of reduced strength .
The association between risk of fractures and muscle strength observed in this study may contribute to the prevention of sarcopenia and fractures in women with breast cancer, especially of the Luminal subtypes, since muscle strength, when reduced, indicates the stage of probable sarcopenia, and HGS and FRAX assess preconditions for these ailments [2, 32]. Sarcopenia is associated with systemic inflammation and with all cancer treatment modalities and may develop equally among breast cancer subtypes [12, 48]. However, patients with hormone receptor-positive tumors (Luminal), which account for approximately 75% of cases, may have a significantly increased fracture risk as they are eligible for endocrine therapy [5, 49]. Estradiol deficiency leads to an imbalance of bone remodeling, which causes bone loss, microarchitectural deterioration, and increased bone fragility. It is also noteworthy that antiestrogenic effects can lead young patients to menopause, which is the main cause of bone loss in women .
In the present study, the muscle quantity, measured by the ASMI, was the only sarcopenia phenotype whose fracture risk was not associated in any of the analyses performed. There are controversies regarding the relationship between muscle mass and the risk of falls and fractures [38, 50, 51]. Harvey et al.  observed that ASM, obtained by DXA, contributed minimal predictive information for falls and fractures in postmenopausal women. A cohort study in elderly males demonstrated that ASM and tests of muscle strength and physical performance predicted fracture risk, regardless of FRAX and fall history; however, the inclusion of BMD, either directly or as part of FRAX, attenuated the association between ASM and fracture prediction .
Evidence suggests that DXA-derived ASM may not contribute to the prediction of falls and fractures, especially when considering femoral neck BMD, as seen in the present study [50, 51]. This tool does not measure ASM directly, as it reflects a body compartment that is neither fat nor bone, within the upper and lower limbs. In this way, it only estimates muscle mass, which ends up including skin, connective tissues, and water, in addition to minerals, proteins, non-fatty lipids, and soft tissue carbohydrates [50,51,52]. In addition, soft tissue can influence the measurement of BMD by DXA, since its mass is incorporated into BMD calculation equations .
The technical aspects of DXA also help to understand the positive association between body mass and ASMI found in the present study, despite the predominance of excess body fat in the population evaluated. Tissues quantified by DXA (bone mass, lean mass, and fat mass) are components of total body mass and their values are derived from it [51, 52].
After insertion of adjustment variables, TUGT did not remain associated with the risk of fracture obtained by FRAX. According to the EWGSOP definition, TUGT is an indicator of the severity of sarcopenia, which means it should be compromised after reduced strength and muscle mass . Such results were not observed, since the participants showed a predominance of adequate HGS, ASMI, and TUGT, which may have contributed to the loss of association between TUGT and fracture risk. This finding demonstrates that, in this population, age was the most important factor for physical performance, which is expected .
The high prevalence of adequate sarcopenia phenotypes and the low risk of fractures in the sample evaluated can be explained by most patients not having started treatment, in addition to them all being free of endocrine therapy. In fact, it is known that breast cancer treatment is one of the main factors that lead to muscle tissue depletion and increased risk of fractures . Nevertheless, a portion of the population analyzed already had a high risk of fractures and probable sarcopenia, in addition to compromised BMD (osteopenia and osteoporosis). Such findings demonstrate the importance of early assessment of these conditions in women with breast cancer, especially the Luminal subtypes, since they can be worsened after treatment .
The impairment of sarcopenia phenotypes and the increased risk of fractures are also influenced by sociodemographic characteristics and habits and lifestyle [54, 55]. Age is a recognized risk factor for both conditions, since aging is characterized by a reduction in muscle and bone mass [54, 55]. In the population studied here, age was inversely associated with muscle strength and positively so with the duration of the TUGT, which indicates bad physical performance.
Similarly, excessive alcohol consumption impairs protein synthesis, and exposure of muscle tissue to ethanol results in autophagy, while smoking can increase muscle fatigue, leading to protein metabolism disorders . On the other hand, the practice of physical activity is useful for the recovery of mitochondrial metabolic function, reducing the expression of catabolic genes and increasing protein synthesis .
Regarding the influence of lifestyle habits on fracture risk, there seems to be a decrease in bone formation in individuals with excessive alcohol consumption, in addition to a greater risk of falling when drunk . As for smoking, the influence on bone health occurs through different mechanisms. Among these are impaired calcium absorption and vitamin D metabolism, involved in bone formation, and increased levels of free radicals, not to mention nicotine itself, which can reduce estrogen production in women . In this study, we did not consider alcohol consumption and smoking habits in the adjusted models, since they are part of the FRAX assessment items. However, the level of physical activity was included as an adjustment variable, given its importance for the outcome evaluated.
In our study, most women had never used alcohol or cigarettes, which may have contributed to the low prevalence of impaired sarcopenia phenotypes and low risk of fractures. However, most were insufficiently active. The IPAQ, the instrument used to measure this variable, takes into account the performance of activities in the last week, and after diagnosis, patients often reduce daily activities, in addition to often receiving a recommendation to rest during chemotherapy and radiotherapy, and after surgical treatment . These factors may have contributed to the low prevalence of sufficiently active women observed.
As for clinical features, Rathnayake et al.  observed significant differences between pre- and post-menopausal women in the phenotypes of sarcopenia – muscle strength, assessed by the HGS test, amount of muscle, measured by the ASMI, and physical performance, obtained by gait speed – and in BMD, in which post-menopausal women had worse results. However, there was no correlation between sarcopenia phenotypes and time of menopause in the population evaluated. We hypothesize that this result may be associated with the predominance of overweight and adequacy of the sarcopenia phenotypes found.
Clinical factors related to breast cancer also influence the risk of fractures, since the prescribed treatment depends on the histological type and molecular subtype of breast cancer (Luminal A, Luminal B, HER2 + , and triple-negative) . Patients in the middle (IIB) or advanced (IIIA, IIIB) clinical stage are the most affected in relation to BMD, probably because of the increase in the production of pro-inflammatory cytokines by the tumor and as a response of the organism, which increases bone resorption . Such factors still exert catabolic effects on muscle tissue, which can compromise muscle strength and muscle mass [3, 4].
Much like sociodemographic and lifestyle variables, time of menopause and clinical variables, such as time of diagnosis, clinical staging, and type of treatment, did not interfere in the association between muscle strength and fracture risk in the women evaluated.
As for nutritional status variables, it has been reported that anthropometric measurements can be positively associated with sarcopenia phenotypes, since they are not able to compartmentalize the constituents of total body mass . On the other hand, body composition parameters are closely related to this disease since it involves the reduction of skeletal muscle mass. Fat mass, when elevated, can promote fat infiltration into skeletal muscle, negatively affecting muscle quality .
Muscle mass also exerts a protective effect against increased fracture risk, through molecular signaling and regulation of hormone levels and bone anabolic factors . While the accumulation of fat promotes the differentiation of adipocytes, it induces the secretion of hormones (adiponectin, leptin, and sex hormones) and produces pro-inflammatory cytokines, which modulate the osteoblast-osteoclast interaction, given that excess visceral fat induces greater inflammation, associated with osteoclastogenesis and bone loss .
This study observed a positive correlation between the variables of the fat mass compartment and ASMI, which can be explained by the limitation of DXA in measuring muscle mass, as discussed above, as well as in quantifying VAT separately. DXA assesses VAT by estimating the amount of subcutaneous fat in the android region, which is subtracted from the total fat mass of this region, thus limiting its interpretation . Another point to be discussed is the inability of DXA to differentiate the amount of fat infiltrated in the muscle from the total muscle mass .
As a contribution, this study demonstrated a relationship between HGS and FRAX, which optimizes the patient assessment process and supports early interventions and strategies, based on simple tools suitable for inclusion in assessment and clinical follow-up protocols. Compared to other tools that evaluate sarcopenia phenotypes, HGS is easy to use in clinical practice, in addition to being low-cost, portable, and not requiring specialized equipment and professionals. Because of these characteristics, its use as part of the routine is recommended in cancer patients .
Thus, our results suggest that serial HGS measurements may help to identify women with breast cancer at high risk of fractures. Longitudinal studies are needed to determine whether incorporating muscle strength measures into fracture risk assessment tools would improve predictive accuracy.
This study has some limitations. It has a small sample, not representative of the general population of women with breast cancer, as it was carried out with a group of women from a single outpatient clinic, from the secondary service of the public health system. It does, however, have a homogeneous and controlled sample, which contributes to the validity of the results presented here. In addition, the proposal to assess the relationship between sarcopenia phenotypes and fracture risk in women with breast cancer is an innovative one, not yet described in this population. Another limitation is the possibility of overestimating sarcopenia phenotypes, since there are no cutoff points for these parameters in the literature for cancer patients.