Second-hand smoke (SHS) is not an established risk factor for breast cancer. We examined exposure to SHS from parents during childhood and breast-cancer risk overall and by oestrogen- and progesterone-receptor status in the Norwegian Women and Cancer Study. Furthermore, we utilized our nationally representative prospective cohort study to estimate the fraction of breast cancer attributable to parental SHS during childhood.We followed 45 923 never-smoking women, aged 34–70 years, who completed a baseline questionnaire between 1991 and 2007 through linkages to national registries through December 2018. We used Cox proportional-hazards models to estimate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). We estimated the attributable and the population attributable fraction of breast cancer with 95% CIs.Pheterogeneity = 0.31) and progesterone (Pheterogeneity = 0.95) receptor status. For women exposed, the attributable fraction was 10.3% (95% CI: 1.8–18.0), whereas the population attributable fraction of breast cancer was 7.0% (95% CI: 1.0–13.0).During a mean follow-up of 19.8 (6.8) years, 2185 women developed invasive breast cancer, confirmed by histology. Women exposed to SHS from parents during childhood had an 11% higher (95% CI: 1.02–1.22) risk of breast cancer compared with those who were not. No difference was found for oestrogen (Our results suggest that 1 in 14 breast-cancer cases could have been avoided in the absence of SHS exposure from parents during childhood in a population of never-smoking women. The cancer burden attributable to SHS may be underestimated. Key MessagesWorldwide, <10% of women are daily smokers, whereas a high proportion are exposed to second-hand smoke (SHS)  during childhood.Our main finding suggests that 1 in 14 breast-cancer cases could have been avoided in the absence of SHS exposure from parents during childhood in a population of never-smoking women.The burden of breast cancer attributable to SHS exposure from parents estimated in the present study supports the notion that breast-cancer research and prevention efforts should have a lifetime approach.Public health agencies that have not recognized SHS as an established risk factor for breast cancer should reconsider the available evidence and update their conclusions.The World Health Organization Framework Convention on Tobacco Control, Article 8, protection from exposure to tobacco smoke, should be fully implemented and enforced globally.Globally, female breast cancer is now the most commonly diagnosed cancer with an estimated 2.3 million new cases (11.7%) in 2020.Worldwide, ∼25% of men and 5% of women were daily smokers in 2015.,,Whereas active smoking is an emerging risk factor for breast cancer, the evidence is more inconsistent for exposure to SHS and risk of breast cancer.We have previously reported that women who were ever-smokers or never-smokers exposed to SHS both had a higher risk of breast cancer compared with those not exposed.As pointed out by Jha,,The Norwegian Women and Cancer Study cohort profile has been previously described in detail.n = 172 478), were the baseline population. The overall response rate was 52.7%. We excluded women with prevalent cancer (n = 6666), who had emigrated (8), who died before start of follow-up (11), who were born after 1957 (n = 3169), who had missing information or were ever-smokers (n = 107 083) or had missing information on exposure to SHS from parents during childhood (n = 9602). Altogether, 8542 women with breast cancer were excluded in this process. The analytical cohort comprised the 45 923 remaining women.Women who completed a questionnaire during three waves of data collection, namely 1991–1992, 1996–1997 and 2003–2007 (2), reproductive and lifestyle factors. Most questionnaires asked about exposure to SHS during childhood, although in two slightly different versions: ‘Did any of the adults smoke at home when you were a child?’ . If, yes, ‘Mother, father, both, others’; or ‘Did any of your parents smoke at home when you were a child?’ . If yes, ‘How many cigarettes did they smoke per day in total?’ Questions about the intensity of SHS exposure (number of cigarettes smoked by the parents) were only asked in a few questionnaires and not considered in this analysis. Almost half of the women were asked at enrolment about current SHS exposure at home from a partner. We dichotomized the women as exposed to SHS by parents during childhood or not. The latter group is the reference group throughout the paper.The baseline questionnaires elicited information about years of education, current height and weight for the calculation of body mass index  in the International Classification of Diseases, Tenth Revision, and according to oestrogen and progesterone tumour-receptor-status categories  based on information from the registry. We calculated person-years from the start of follow-up to the date of any incident cancer diagnosis , emigration, death or the end of follow-up (31 December 2018), whichever came first.http://seer.cancer.gov/stdpopulations/).We calculated percentages (%) or means with standard deviation (± SD) for the distribution of selected characteristics of the study population. We estimated crude breast-cancer incidence rates overall and according to the SHS-exposure group, by dividing the number of cases by the total number of person-years. We then age-adjusted the rates to the world standard population (n = 374), PR status (n = 433) or both (n = 10) were excluded from the corresponding analyses. Heterogeneity in risk by SHS between the tumour hormone-receptor-status categories was assessed using a Wald test.We used the Cox proportional-hazards regression model with age as the underlying timescale to estimate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between exposure to SHS from parents during childhood and risk of breast cancer overall, and according to oestrogen and progesterone hormone-receptor statuses. Subsequently, we performed competing risk analysis using cause-specific hazard models for time to hormone-receptor-status breast-cancer outcomes, with censoring at diagnosis for any breast-cancer cases with a receptor status other than that being considered.We examined whether each of the following selected covariates of birth cohort, education level, age at menarche, a combination of age at first birth and parity, BMI, physical activity, alcohol consumption or menopausal status changed the HR estimate by >5%. None of them did.2, ≥25 kg/m2), physical-activity score , alcohol consumption  all at enrolment, and menopausal status , changing to postmenopausal status during follow-up with available information or at age 51 years, whichever came first] selected factors. The proportional-hazards assumption was tested using Schoenfeld residuals and was found to hold.,We present age-adjusted HR estimates throughout the paper. Using the Wald test, we tested for heterogeneity in the SHS—breast cancer association by eight .To our knowledge, our study is the first to estimate the fraction of breast cancer in never-smokers attributable to exposure to SHS from parents during childhood. Compared with those not exposed, we observe a higher breast-cancer risk for women exposed. This higher risk seems to be of a similar magnitude for the different tumour hormone-receptor types. Also, the magnitude of the higher breast-cancer risk was consistent when we stratified by eight selected variables. Finally, we estimated that in women exposed, 1 in 10 and, in the population of never-smokers, 1 in 14 breast-cancer cases could have been avoided in the absence of SHS from parents during childhood. These numbers are of a magnitude that can explain some of the global increase in breast-cancer incidence.In our 2016 report, the majority (65%) of women were ever-smokers. We estimated that the fraction of breast cancer in Norway attributable to ever-smoking was 12%, whereas it was 3% for any SHS exposure.in utero (16%) and during childhood/adolescence from birth to 18 years (17%). This report from the Sister cohort study conducted in the USA and Puerto Rico did not find an association with either active or adult SHS exposure and breast-cancer risk. All analyses concerning SHS exposures were restricted to never-smoking women.Among the seven cohort studies,The reports within the UK Million Women Study,,,,,All but two,,,For the cohorts that gave information on SHS exposure during childhood in never-smokers, compared with our study, the proportion was lower in two,,,,,Results from 13 cohort studieset al., in their meta-analyses, included only the 11 cohort studies, women exposed to SHS had a 7% higher risk of breast cancer overall compared with those who were not.In 2008, Johnson and Glantz noted that the evidence from epidemiological studies on SHS and risk of premenopausal breast cancer was in 2005 stronger than that for SHS and lung cancer in 1986.,One major strength of this study is that we have a high number of incident breast-cancer cases with known SHS exposure from parents during childhood in a population of never-smokers. This allowed us to focus on the breast-cancer risk among never-active-smoking women, which describes most women globally. Another strength is that we were able to estimate the burden of breast cancer based on individual exposure data and not on country prevalence. Also, the study population is representative of the Norwegian middle-aged female population, according to both smoking exposureWe consider it a strength that we were able to address four  of the seven research questions on smoking and breast-cancer risk listed in the Surgeon General's report,Furthermore, we have virtually complete follow-ups through the National Population-based registries. Since our youngest enrolment age was 35 years, it is unlikely that the women have started to smoke during follow-up, as very few women initiate smoking after this age.The main limitation of the present study is the lack of detailed information, as calendar time, duration and intensity, regarding the SHS exposure from parents. Moreover, we had information on current SHS exposure from spouses at enrolment for fewer than half of the women. We decided to include them in the reference group, which may have attenuated our results. Furthermore, we did not define what we meant by ‘childhood’ in our questionnaires. There may be some residual confounding due to the examined factors or to other factors that we did not measure.et al.The previously cited expert reportsn = 165) of all parties had implemented some measures to protect people from tobacco smoke (Article 8). However, most countries had not banned smoking in private homes or private vehicles when children are present.The women in our study were born between 1927 and 1957. The youngest women in our cohort were teenagers in the 1970s—a decade with no general concern about possible negative health effects from SHS exposure. In 2005, the WHO Framework Convention on Tobacco Control entered into force.In conclusion, we observe that in a population of never-smoking women, those exposed to SHS from parents during childhood had a higher risk of breast cancer than those who were not. Our results suggest that in women exposed, 1 in 10 and, in the population of never-smokers, 1 in 14 breast-cancer cases could have been avoided in the absence of SHS from parents during childhood. We note that the global cancer burden due to SHS may be underestimated.The study was approved by the Regional Committee for Medical and Health Research Ethics (REK NORD).None.Data available on request. The data underlying this article will be shared upon reasonable request to the corresponding author.


The causal impact of body fat distribution on female-specific cancers is largely unknown. For the first time we used a two-sample multivariable Mendelian randomization (MR) approach to elucidate the role and causal relations of body composition assessed by segmental bioelectrical impedance analysis on the risks of breast, endometrial and ovarian cancers and their subtypes. We found that abdominal fat content increases the risk for ovarian cancer and its endometrioid and clear cell subtypes independent of overall fat content. General adiposity has a protective effect on risk of breast cancer and its ER- and ER+ subtypes but increases the risk for endometrial cancer, ovarian cancer, and the endometrioid ovarian cancer subtype. This study extends the literature by addressing specifically the causal role of visceral fat on female-specific cancers.Background: Mounting evidence shows that adiposity increases female-specific cancer risk, but the role of body fat distribution is less clear. We used a two-sample Mendelian randomization (MR) approach to elucidate causal relations of body fat distribution to the risks of breast, endometrial and ovarian cancers and their subtypes. Methods: Body composition was assessed using segmental bioelectrical impedance analysis, yielding trunk, arm, and leg fat ratios  and BMI including 195,043 and 434,794 European women, respectively. The sample sizes for the outcomes ranged between 58,396 and 228,951. Causal effects were estimated per one standard deviation increment in the respective exposure within the radial regression framework. Robust sensitivity analyses were performed to verify MR assumptions. In a multivariable MR setting, the proportion of risk attributable to overall and abdominal fat content was assessed. Results: TFR, which represents abdominal fat content, was associated with ovarian cancer and its clear cell and endometrioid histotypes independent of overall fat content. BMI was inversely associated with breast cancer and its ER− and ER+ subtypes, but positively with endometrial cancer and ovarian cancer, including its endometrioid histotype. These estimates were confirmed using AFR as proxy for overall body fat. Conclusions: Visceral adiposity seems to be a driver of elevated ovarian cancer risk, particularly of the endometrioid and clear cell ovarian cancer histotypes. General adiposity decreases the risk of breast cancer but increases the risk of endometrial and ovarian cancer. Breast cancer is the most commonly diagnosed female cancer and endometrial as well as ovarian cancer incidence rank sixth and eighth, respectively, underscoring the global impact caused by these cancers . SeveralA growing body of evidence suggests that body composition may play an important role in site-specific cancer development ,18,19, bThe present study is the first MR study using bioelectrical impedance analysis measurements of body fat distribution in addition to BMI as potential risk factors for female-specific cancers. We sought to generate more comprehensive and robust evidence of the impact of trunk, arm, and leg fat ratios  on breast, ovarian, as well as endometrial cancer including their histotypes based on univariable and multivariable MR analyses.A two-sample MR design allows for the assessment of a causal relationship using genome-wide association studies (GWASs) derived from different populations for the exposure and the outcome of interest. Three key assumptions need to be satisfied in a MR study: genetic instruments (i) must be associated with the respective risk factor; (ii) must not be associated with any measured or unmeasured confounder of the exposure-outcome association; and (iii) must influence the outcome only through the exposure. Details on the MR-design can be found elsewhere ,24. In tOur analytic approach included: (i) extraction of potential genetic instruments; (ii) conducting univariable and multivariable MR analyses to assess overall and direct effects; (iii) applying several sensitivity analyses to assess different patterns of pleiotropy and validate MR assumptions.Regarding the amount of overall fat and for comparisons with prior MR-studies, we used BMI. To discriminate fat stored in different parts of the body, we used the fat ratio indexes TFR, AFR, LFR assessed by a segmental body impedance analysis (BIA) and calculated by dividing the fat mass in the respective body segments with total body fat mass . SegmentGenetic instruments for BMI were obtained from a GWAS (GIANT consortium and UK Biobank) of 434,794 European women  Table 1Table 1. As outcomes we considered breast, ovarian, and endometrial cancer. Additionally, we performed subgroup analyses of ER-positive (ER+) and ER-negative (ER−) breast cancer subtypes and the histotypes clear cell, endometrioid as well as high and low grade serous epithelial ovarian cancers.The breast cancer GWAS was obtained from BCAC with 122,977 cases  and 105,974 controls  Table 2Table 2. We selected single nucleotide polymorphisms (SNPs) associated with the respective body composition measure below the genome-wide association threshold of We calculated the statistical power according to Brion et al.  dependenR2=0.05) .As principal analysis, we performed the radial inverse-variance weighted (IVW) regression with modified second-order weights. This approach provides large statistical power and allows even for balanced pleiotropy . To account for directional horizontal pleiotropy, we performed radial MR-Egger regression with modified second-order weights and tested the deviation from zero applying Egger’s intercept test .Since the analyses were carried out iteratively, in each step we calculated SNP-specific Q-statistics and performed a leave-one-out-analysis to identify and remove outliers. Additionally, several global heterogeneity statistics were calculated and tested regarding the appropriate methods for the relationship between body composition and cancer types .Potential horizontal pleiotropy was assessed using robust MR approaches. The weighted median method provides a consistent estimate even if up to 50% of selected genetic instruments are invalid. The MR-PRESSO approach consists of three components, namely a global, outlier, and distortion test. The global test identifies horizontal pleiotropy based on the observed residual sum of squares (RSSobs). The outlier test corrects, if present, horizontal pleiotropy via outlier removal identified by SNP-specific RSSobs. The distortion test compares estimates before and after outlier removal. A many weak instrument analysis was done using the Robust Adjusted Profile Score, allowing instruments to be weak.To compare the direct effects and separate out what proportion of female-specific cancer risk is due to general and visceral fat content, we performed MVMR analyses. AFR and TFR were utilized as proxies for the degree of overall and abdominal fat content, respectively. The conditional F-statistics were at least 25.9 implicating absence of weak instrument bias. Horizontal pleiotropy was quantified and tested using the modified Cochran’s Q-statistics, while directional pleiotropy was investigated using MR-Egger intercept tests . Causal All estimates depict ORs per one standard deviation (SD) increments in the exposures. The type I error was set to As genetic instruments we selected 297 BMI-, 202 TFR-, 116 AFR-, and 166 LFR-related SNPs . For BMIThe Radial IVW models with modified second-order weights as the main method (point estimates are subsequently referred to as OR_IVW and are given per 1 SD increment of the respective exposure) found an inverse association between BMI and breast cancer  . These rAlthough there was evidence for substantial heterogeneity  , the strAfter mutual adjustment, the inverse effect of AFR with breast cancer   despite , 0.94]) .The multivariable analyses confirmed the protective effects of AFR on ER−  . No furtAlthough there was not a clear association with ovarian cancer, consistently positive relations were observed of both BMI and AFR to endometrioid ovarian cancer, with ectively . Regardifindings .In the multivariable setting, the association between AFR and the endometrioid ovarian cancer remained positive (Robust IVW Although no directional pleiotropy was detected by MR-Egger intercept tests, there was evidence for substantial heterogeneity quantified by Q-statistics in the multivariable models . HoweverOur MR study showed that visceral adiposity increased the risk of breast cancer, mainly ER+ breast cancer, and the risk of ovarian cancer, mainly clear cell ovarian cancer. Relations of genetically predicted visceral adiposity to breast and endometrial cancers were weaker than those with general adiposity. However, visceral adiposity appears to play a more important role than general adiposity for the risk of ovarian cancer, in particular the clear cell and endometrioid cancer subtypes. The findings confirmed a causal protective effect of general adiposity on breast cancer risk. This effect could be ascribed to associations with both ER- and ER+ breast cancers and was confirmed in multivariable analyses. In contrast, general adiposity was a strong causal risk factor for endometrial cancer and a weaker causal risk factor for ovarian cancer, in particular for the endometrioid histotype. LFR was not related to overall cancers but showed effects in the same direction as AFR on ER+ breast cancer and clear cell ovarian cancer.Epidemiologic studies reported a positive relationship between obesity and postmenopausal breast cancer and an inverse association with premenopausal breast cancer ,31,32,33The evidence relating body fatness to ovarian cancer and its subtypes is inconclusive . The WCRObese adipose tissue seems to create a pro-oncogenic environment. Specific biological mechanisms to explore the link between obesity and cancer risk are centered along metabolic and endocrine consequences of body fat accumulation. Changes in the metabolism of sex hormones, insulin and insulin-like growth factor signaling, inflammatory effects and Adipokine-related effects were identified. According to an IARC working group, the evidence for a role of sex hormones and chronic inflammation was judged as strong, while the evidence for insulin and IGF was moderate . Among oOur study has a number of considerable strengths. Using both BMI and AFR we could replicate the findings of a previous MR study, which provided support for our estimates. While BMI approximates total fat content, the fat ratio indexes used in our study discriminated between adipose and lean mass and are therefore more reflective of actual fat mass and body fat distribution. All exposures were modelled as continuous variables to avoid residual confounding and to boost statistical power. Sufficiently large F-statistics reduced the potential for weak instrument bias. The broad range of robust methods allowed us to strengthen our findings by considering different patterns of pleiotropy. The multivariable approach allowed us to distinguish between the direct effects of overall and abdominal fat content.Our study also has certain limitations. TFR considers the fat content of the entire torso rather than that of the abdomen only, which may have underestimated causal associations. MR analyses assume relationships to be linear. Quantitative estimates may be misleading if the true relationship is non-linear; although estimates are still reflective of the presence and direction of the population-averaged causal effect . Our anaIn conclusion, our MR study shows a protective effect of general adiposity on risk of breast cancer and its ER- and ER+ subtypes. In contrast, general adiposity increases the risk for endometrial cancer, ovarian cancer, and the endometrioid ovarian cancer subtype. Visceral adiposity is related to an increased risk for ovarian cancer and its endometrioid and clear cell subtypes and is suggestively associated with increased risk of breast cancer and its ER+ subtype. These results extend the literature by addressing the role of visceral adiposity regarding female-specific cancers and support previous findings on general adiposity. Thus, it can be concluded that different body fat distributions lead to different risk profiles and not obesity per se, but rather body fat distribution should be taken into consideration in connection with the risk of female-specific cancers.


The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear.This Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women.CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio.As primary genetic instrument, we used a genetic variant in the P = 2.5 × 10−3), endometrial cancer overall , and endometrial cancer of the endometrioid histology subtype . There were suggestive associations with breast cancer overall , ovarian cancer of the endometrioid subtype , and stomach cancer , but no significant association with other cancers.Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; This study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women. Estrogens are a class of steroid hormones with a fundamental role in a wide range of physiological processes, such as menstrual cycle regulation, reproduction, preservation of bone density, and modulation of brain function . 17β-estMendelian randomization (MR) is a technique to provide evidence on causal relationships by exploiting genetic variants having a robust association with the exposure as instruments to predict the effect of the exposure on disease risk , 15. TheCYP19A1, which encodes aromatase, an enzyme that converts androgens to estrogens. Aromatase is expressed in the gonads, placenta, adipose tissue, brain, and other tissues. Rs727479 and an SNP in complete linkage disequilibrium with this genetic variant in the CYP19A1 gene (rs7173595) have previously been shown to be strongly associated with serum E2 levels in genome-wide association studies (GWAS) of postmenopausal women  rs727479 in al women  and men  gene rs73595 haveal women . This SNal women  and whicWe obtained summary statistics GWAS data for breast, endometrial, and ovarian cancer from the Breast Cancer Association Consortium , a meta-We additionally estimated the associations of the E2-associated SNPs with any and 20 site-specific cancers in 198 825 unrelated women (37 to 73 years of age at the baseline assessment) of European descents in the UK Biobank cohort using logistic regression with adjustment for age and 10 genetic principal components, as described previously . InformaAll studies have been approved by a relevant ethical review board, and participants have provided informed consent. The MR analyses were approved by the Swedish Ethical Review Authority.CYP19A1 gene region with the cancer outcomes were estimated using the Wald ratio method. For the MR analyses of serum E2 instrumented by 5 SNPs, 3 MR methods with different assumptions were applied. These included the multiplicative random-effects inverse variance weighted, weighted median, and MR-Egger methods (P < 0.0025 (P = 0.05/20 site-specific cancers). Associations with a P value between 0.0025 and 0.05 were regarded suggestive. The MR-Base platform  as well as with endometrial cancer overall  and the endometrioid histology subtype  (P = 0.02) and ovarian cancer of the endometrioid subtype  (P = 0.05) but no association with the other site-specific cancers  . There w = 0.02) . In UK B = 0.02) . There w cancers .P values > 0.05). Given the lack of association of this 5-SNP instrument with the positive control outcomes ER-positive breast cancer and endometrial cancer, we did not proceed with the corresponding analyses for 20 site-specific cancers using UK Biobank data, as these variants did not seem to be valid instruments for E2.MR analyses of serum E2 instrumented by 5 SNPs showed no significant association with breast, endometrial, or ovarian cancer and their subtypes based on consortia data and 3 different MR methods  from Hawaii  and therefore we may have overlooked weak associations. Finally, higher genetically predicted E2 levels were associated with lower serum testosterone. Given that genetically predicted serum testosterone is positively associated with breast and endometrial cancer risk , the risIn conclusion, these MR findings support a causal role of endogenous E2 levels in ER-positive breast cancer and endometrioid endometrial cancer. Nevertheless, we found no evidence of a strong association of endogenous E2 levels with a broad range of other site-specific cancers in women.


Early detection of breast cancer is effective for prolonging survival, but the participation rate in breast cancer screening among target Japanese women remains low. This study examined the relationships between tendencies in decision-making under conditions of uncertainty, health behaviors, demographics, and breast cancer screening participation in Japanese women.Secondary analysis was performed using data from the 2017 Keio Household Panel Survey (KHPS). The study population consisted of 2945 households. Data were obtained from the KHPS for women aged 40 years or older. Breast cancer screening participation in the past year, risk aversion, time preference, health behaviors , and demographic variables were analyzed.p = 0.043), medical treatment received in the past year , higher self-rated health , living above the poverty line , and having children . Factors significantly associated with non-participation in breast cancer screening were smoking , alcohol consumption , being self-employed , and being unemployed . No significant relationship was observed between time preference and screening participation.Data from 708 women were analyzed. Among the respondents, 28.8% had attended breast cancer screening in the past year. Factors found to significantly contribute to breast cancer screening participation included higher risk aversion (odds ratio [OR], 2.34; 95% confidence interval [CI] = 1.03–5.32; The results indicate that women who recognize the actual risk of developing breast cancer or have high awareness of breast cancer prevention tend to participate in breast cancer screening. Barriers to screening participation are not working for an organization that encourages screening and low income. Breast cancer is the most common cancer among women worldwide . In JapaMammography is the most effective breast cancer screening tool and can help decrease breast cancer mortality by enabling earlier diagnosis and treatment –5. SincePrevious studies have revealed that breast cancer screening participation is associated with health-related lifestyle and behavioral factors, such as knowledge or health literacy about breast cancer –18, smokEconomic factors are also barriers to breast cancer screening participation , 25. AccDeterminants of preventive health behaviors are receiving increased attention in the field of behavioral economics , 34. PreAnother tendency in behavior or decision-making under conditions of uncertainty is risk aversion. This concerns the attitude toward risk that people have when deciding to use disease prevention services to decrease the probability of disease or death , 36. EveCommunities in Japan are struggling with improving breast cancer screening rates. Given that women who attend breast cancer screening tend to have healthy habits, strategies have usually been proposed for people with poorer health behaviors or who are not interested in health behaviors. However, such strategies would not be fully effective considering the low rate of breast cancer screening participation in Japan. More effective tactics are needed both to encourage women to participate in breast cancer screening in order to decrease their risk of breast cancer-related health problems in the future and to improve screening participation rates.Against this background, in this study we examined the relationship between decision-making tendencies under conditions of uncertainty and breast cancer screening participation among Japanese women. We also analyzed the relationship of health behaviors and demographics with breast cancer screening to explore more effective strategies for increasing the breast cancer participation rate in Japanese women.This cohort study is a secondary analysis of quantitative data from the Keio Household Panel Survey (KHPS). The KHPS survey, conducted by Keio University, provides representative data from panel surveys of Japanese households .Briefly, the KHPS was approved by the Ministry of Education, Culture, Sports, Science and Technology in Japan and has been conducted annually since 2004, surveying a total of 4005 households nationwide. A stratified two-stage sampling method is used for the survey. KHPS respondents in 2004 were men and women born between 1935 and 1984. The demographic characteristics of the respondents are representative of Japanese households nationwide. The KHPS questionnaire includes items on place of residence, basic demographic data , employment status, health status, health-related behaviors, and household economic status.All participants in the KHPS were informed about the purpose of the research, potential use of their data, the survey methodology, data anonymity, strict protection of individual data, and secondary use of data. The KHPS data are collected by mail, Internet survey, and visit survey by researchers. Applications for secondary use of these data must be submitted to and approved by Keio University, with assurance provided that ethical considerations will be met. Before we started this study, Keio University approved our use of the KHPS data in accordance with our application and assurance that all ethical considerations will be met. Accordingly, Keio University then provided us with the KHPS data sets.The empirical analysis in this study primarily used the 2017 wave of the KHPS and partially relies on the 2004 wave for basic demographic data. The sample analyzed included women aged 40 years or older, which corresponds with the recommended age for breast cancer screening in Japan. No upper limit on the recommended age for breast cancer screening has been set in Japan.The aim of the study was to explore the relationships between decision-making tendencies under conditions of uncertainty, health behaviors, demographics, and likelihood of breast cancer screening participation in Japanese women.The primary outcome was breast cancer screening participation in the past year (participated or did not participate).Explanatory variables were variables related to risk aversion, time preference, health behaviors, and demography. Risk aversion was assessed using a question about deciding whether to take an umbrella out depending on the percentage likelihood of rain in a weather forecast. Time preference is the amount of future utility that is equivalent to the current utility of consuming a good or service, and describes the preference for immediate utility (satisfaction or happiness one derives from consuming a good) over delayed utility. An individual with a high rate of time preference places more emphasis on the present and discounts the future relatively heavily , 40, 41.Ratios of time preference and risk aversion were obtained as percentages, with a lower time preference ratio indicating lower time preference and a higher risk aversion ratio indicating higher risk aversion. To account for relative poverty, yearly household disposable income was calculated by dividing household income by the square root of household size and then dividing participants into two groups: “living below the poverty line”  and “living above the poverty line” . Age was calculated from year of birth.t-tests were performed as a preliminary analysis to compare differences in risk aversion, time preference, SRH, and sleep duration between the groups. Subsequently, logistic regression analysis was performed and odds ratios were calculated to identify the factors associated with breast cancer screening participation. Variables that were significant in the univariate analysis were entered into the model as exploratory variables.Frequency (percentage) and descriptive statistics (mean and standard deviation [SD]) were first confirmed for all variables. Chi-squared tests were then performed and adjusted standardized residuals (ASRs) were calculated in a preliminary analysis to compare those who participated in breast cancer screening with those who did not according to age, child status, marital status, level of education completed, type of employment, relative poverty, medical treatment received in the past year, smoking status, alcohol consumption, and weekly physical exercise. Furthermore, p < 0.05 (two-tailed).All statistical analyses were conducted using SPSS Statistics 25.0 for Mac . Statistical significance was set at In 2017, the KHPS questionnaire was distributed to 2945 households, of which 2729 responded (response rate: 92.7%). A total of 708 questionnaires had complete responses and met the inclusion criterion (answered by women aged ≥ 40 years). These responses were analyzed in the course of the present study .Table Of the respondents, almost a third underwent breast cancer screening in the past year. Those in the age ranges of 60–69 years and 50–59 years comprised just over half of all respondents, and those aged 40–49 years comprised almost a quarter. Most lived with families; approximately three-quarters were married and over half had children. Most had not completed university or graduate school. Relatively few were regular employees, whereas more than a third were unemployed. Analysis of health behavior variables revealed that most were non-smokers, more than two-thirds did not consume alcohol, almost a quarter performed weekly exercise, and almost half had received medical treatment in the past year. Mean time preference was 0.17 ± 0.15 and mean risk aversion was 0.60 ± 023.t-tests were performed to examine the differences in explanatory variables according to breast cancer screening participation.Table 2 = 3.91, p < 0.048), child status , level of education completed , type of employment , relative poverty , smoking status , and alcohol consumption . Breast cancer screening participation during the past year was more likely among those who lived with family (ASR = 2.0), had children (ASR = 3.7), had completed junior college or vocational school (ASR = 3.2), had precarious employment (ASR = 5.4), had received medical treatment in the past year (ASR = 2.3), were a non-smoker (ASR = 5.7), and did not consume alcohol (ASR = 4.1). Conversely, breast cancer screening participation was less likely among those who were self-employed (ASR = 5.5) and those who were living below the poverty line (ASR = 3.1).Chi-squared tests showed significant differences in breast cancer screening participation according to family type (χt-tests) were subjected to logistic regression analysis, with age and region of residence used as control variables , receiving medical treatment in the past year , having a higher SRH , living above the poverty line , and having children . Conversely, factors found to contribute significantly to non-participation in breast cancer screening were being a smoker , alcohol consumption , being self-employed , and being unemployed . Time preference was not found to be significantly associated with breast cancer screening participation.Factors found to significantly contribute to breast cancer screening participation in the past year included being more risk averse  in our sample compared with that within the past 2 years in the Comprehensive Survey of Living Conditions in 2016 44.9%) [% [9]. ThOur results indicate that women with higher risk aversion might actively participate in breast cancer screening to decrease the risk of delayed cancer detection. There is increasing awareness that early detection of breast cancer leads to more effective treatment and thus to a better prognosis. Therefore, women with an accurate perception of breast cancer might undergo breast cancer screening to mitigate their breast cancer risk. A meta-analytic review demonstrated that perceived risk is a predictor of the likelihood of attending breast cancer screening . Women wThe results of the present study also showed that time preference did not significantly affect the likelihood of breast cancer screening participation, unlike the findings of past studies , 36, 46.Smoking and alcohol consumption are risk factors for various cancers, including breast cancer . Past reSeveral studies have demonstrated that frequent visits to medical doctors could increase the opportunities to recommend breast cancer screening and promote awareness of cancer control , 29, 30,Regular employees have been shown to have the highest breast cancer screening participation rate , 56, 57,Our analysis suggests that relative poverty should not be overlooked as a barrier to breast cancer screening. Japan has a universal health insurance system. It does not cover the cost of preventive breast cancer screening in absence of subjective symptoms of breast cancer, in which case the patient must pay out of pocket. However, the system does cover the cost when subjective symptoms are present and the doctor considers breast cancer screening necessary. As a rule, the cost of both self-funded and insured breast cancer examinations depends on the medical institution, but the cost of self-funded examinations is generally between JPY 8000 and JPY 10,000, and the cost of insured examinations is generally between JPY 3000 and JPY 5000 . Income Moreover, the findings of this study suggest that lower income might delay participation in breast cancer screening. Further research is needed to understand the confounders of the association between income and participation in breast cancer screening, such as educational level, accuracy of knowledge about breast cancer, accessibility of information about breast cancer screening, the difficulties in taking time off work for cancer screening and the cost burden of screening, after which effective strategies have to be built. For example, an education program about breast cancer could be implemented in primary care to ensure that no woman is without accurate knowledge of breast cancer screening. Alternatively, a public awareness campaign could be developed to ensure that all women know that screening can help prevent breast cancer.Finally, this study found that having children is associated with participating in breast cancer screening. Women with children have childcare responsibilities, so it is likely that their health awareness is already high and that they undertake preventive health behaviors.This study has several limitations. First, it used cross-sectional data to investigate the associations of breast cancer screening participation with decision-making tendencies under conditions of uncertainty and preventive health behaviors. As such, causality cannot be inferred. Second, the survey data were all self-reported, so the findings may have been affected by response bias , 72. FurThis study used representative data from a panel survey of Japanese households and showed that women who recognize the actual risk of developing breast cancer and women with a high level of awareness of the need to prevent breast cancer are likely to attend breast cancer screening. Healthy preventive behaviors were also associated with participation in breast cancer screening. However, being self-employed, being unemployed, and living in relative poverty would be barriers to participation in screening.


Background: The risks of osteoporosis and breast cancer are increasing in elderly women. Bisphosphonates and denosumab are recommended for treatment of osteoporosis. They have different and overlapping pharmacodynamics and previous studies have shown conflicting results regarding their risk association with breast cancer. We intend to further look into this issue through a comparative study.Methods: Electronic health records of 91,626 women older than 50 years with no previous history of malignancy and no nonbreast cancer during follow-up were retrieved from southern California and retrospectively analyzed using univariate, bivariate, and log-rank tests. Medication use, breast cancer risk, and associated demographic and clinical history were assessed.Results: Over an average of 3.6 years follow-up, the breast cancer relative risks (RRs) counted after 365 days of latency are 1.12  for denosumab ever users and 0.37 (95% CI: 0.21–0.66) for bisphosphonates ever users, when covariates are comparable. The significant difference is supported by the Log-rank test (p = 0.0004). Excluding statins coprescribers, the breast cancer RR is 1.31  in denosumab group and 0.26  in bisphosphonates group. There is a reduced RR in statins ever users , and the breast cancer risk difference is not significant between concomitant denosumab/statins and bisphosphonates/statins ever users with RR 0.65  versus 0.55 , p = 0.692.Conclusions: Our data support an association of lower breast cancer risk with bisphosphonates use in elderly women. We did not observe a lower breast cancer risk in denosumab group; however, our data revealed a potential lower breast cancer risk in denosumab users with concurrent statins use and this requires further study. Seventy-one percent of osteoporotic fractures occur in women, while breast cancer is the most common tumor all over the world.1Currently, bisphosphonates  and denosumab are recommended by United States Preventive Services Task Force (USPSTF) to treat osteoporosis in postmenopausal women younger or older than 65 years.3–5The antiosteoporotic effects of bisphosphonates and denosumab are different: denosumab is more effective and faster in improving bone mass density; but effects of bisphosphonates continue for years after drug discontinuation because they are imbedded in the bone, while denosumab discontinuation fully and rapidly reverse its effects on bone markers and bone mineral density. Denosumab is contraindicated in severe infection, but is preferred in patients with renal failure.6–15 A recent study suggests a potential protective effect of denosumab ever use on breast cancer risk in a cohort of older women previously treated with bisphosphonates.16 It is not clear whether this protective effect is due to lingering effects of previous bisphosphonates use. Denosumab is active in body for only 6 months compared to years of lingering effects from bisphosphonates. This may lead to a speculation that denosumab has no effect on breast cancer in women who took and discontinued it. However, drug side effects may not occur until long time after stopping the medication and cancer can be related to radiation exposure events, which have lasted only minutes. A comparative study of denosumab and bisphosphonates might be helpful addressing this question. An initial epidemiological study based on the Nurses' Health Study (NHS) cohort did not show protective effects of statins on breast cancer, when antiosteoporosis therapy was not considered in either medication or control groups.17Epidemiological studies have also shown that bisphosphonates are associated with variable nonadverse, for example, protective or no related risk toward female breast cancer.Cancer risk reduction using pharmacological means is an attractive modern preventive approach that supplements the classical behavioral prevention recommendations. Studying commonly used drugs such as bisphosphonates and statins as candidate cancer chemopreventive agents has the advantage of usually having a low-risk profile and is associated with much clinical experience.The osteoporosis risk increases after menopause, which is on average by age of 51, and this is also the early starting age antiosteoporosis medications are provided. We set the start of our observation time as age 50 and older.The potential different effects of bisphosphonates and denosumab on breast cancer have not been compared yet. How possibly the drug interaction of antiosteoporosis with statins could further modify breast cancer risk is unknown. Knowledge of these may help decisions on individualized medication best beneficial to patients. We aim to investigate those questions using a cohort, including females 50 years of age or older.This study was approved by the Research Ethics Board of University of California at Los Angeles (UCLA), IRB#16-000581. Inclusion criteria: female and age 50 or older at their first visit, with at least two ambulatory encounters in 1 year. Exclusion criteria: previous diagnosis of cancer in the first encounter and cancer diagnosis other than breast cancer during follow-up.The clinical data were retrieved from electronic health record (EHR) Epic. A 3.6-year duration of chronological clinical information was extracted from the Clarity data base, which has been daily transferred from the Epic application (Chronicles). The requested data output for this project is in nine CSV  format files, including parameters of ICD, SNOMED diagnoses, laboratories, medications, family history, allergies, vital signs, and demographic information. The medications include prescriptions linked to pharmacy fill-up or in-house administration. All HIPAA  identifiers have been stripped from the data sets. These data sets were linked using unique encoded identifiers.In addition to denosumab and bisphosphonates, we also examined possible interactions with two other popular drug classes: hormones and statins. The patients were separated into two mutually exclusive groups, medication group and control group:It includes (1) denosumab, (2) bisphosphonates , (3) statins , and (4) hormones .Hospital visitors who have never been prescribed bisphosphonates, denosumab, statins, or hormones.ICD-9  and ICD-10  codes, which are authoritative tools for disease identification, besides their association with claims and reimbursement, are used to identify breast cancer patients (see (1) Patients who were diagnosed with breast cancer 365 days or later after they were first prescribed any of these four medication groups; (2) patients in the control group who were diagnosed with breast cancer at least 365 days after the first encounter. The following situations are excluded from counting of breast cancer cases to focus on primary breast cancer study, and to exclude situations when denosumab/bisphosphonates are used to treat bone metastatic tumor or myeloma: (1) patients exposed to denosumab or bisphosphonates who have cancer diagnoses other than breast type; (2) patients with breast cancer diagnosis before denosumab or bisphosphonates administration.We examined controlling our comparisons against the following relevant covariates: age, body mass index (BMI), blood pressure (BP), hyperlipidemia, diabetes status, breast cancer family history, and alcohol ever use. Those parameters are extracted from either ICD-diagnosis codes or laboratory measurements or encounter documentation.All data analyses and application of inclusion and exclusion criteria were performed using the R statistical software package (with R Studio).p values  were provided whenever feasible.The univariate and bivariate analyses include a Kaplan-Meier plot and its associated log-rank test, relative risks (RRs), confidence intervals (CIs), and Fisher's exact test, and For each patient in the medication group, we computed the last date of any of the four drugs that they took and added that number to 365 to determine the threshold after which a breast cancer diagnosis gets counted.The UCLA health system has around 180 primary and specialty care practices in southern California. There are 285,254 patients who are aged 50 years or older at their first visit on or after date of January 01, 2012. The visit types include all encounters documented in the Epic EHR, including ambulatory , emergency, emergency to inpatient, and inpatient, etc. 205,952 patients who are older than 50, with at least two ambulatory encounters in 1 year from January 1st, 2012 to July 1st, 2016 in UCLA electronic health system were first sorted out. After excluding male patients and patients who have had previous diagnosis of cancer in first encounter and cancer diagnosis other than breast cancer during follow-up, our cohort includes 92,207 female patients. Excluding patients with cancers other than breast, a total of 91,626 patients enter final analysis .The duration of denosumab and bisphosphonates use in our cohort is mostly around 1–2 years. The number of patients taking the medications and prescription dosage are summarized in p = 0.0085)   .We next examine whether this risk difference between denosumab and bisphosphonates continues to hold in the stratifications of risk factors reflexing general health and physical activity.n = 74,867) who have never been prescribed bisphosphonates, denosumab, statins, or hormones.Of note, in the medication groups of denosumab, bisphosphonates, statins, and hormones, 3218 women out of 26,022 have taken more than one type of the four medications, accounting for 12%  of the aforementioned medication prescribers. The control group is hospital or office visitors (p = 0.6965); the breast cancer risks in bisphosphonates (0.52%), statins (0.65%), and hormone (0.26%) groups are significantly lower than control  [Our data analyses showed that denosumab and control groups have similar breast cancer risk  . The dif<0.0002) . In bloo<0.0002) . This haJoint use of statins is associated with lower breast cancer risk in the denosumab group but not in the bisphosphonates groupp < 0.001%). When we looked at the breast cancer risk in joint medication users, we found that joint denosumab and statin use showed a lower breast cancer RR compared to denosumab ever use , but the association is not statistically significant. The wide 95% CI (0.16–2.58) observed in joint denosumab and statin users is due to few (n = 2) cancer cases observed. In contrast, joint use of bisphosphonates and statins show a breast cancer RR slightly higher than single medication ever use, but not statistically significant  [The concurrent statins use is 29% (224/778) in denosumab groups and 40% (919/2326) in bisphosphonates group (26–1.16) .The hormone group in this cohort is characterized by lowest proportions of hyperlipidemia, diabetes, hypertension, and highest proportion of lean body figure (BMI less than 25) compared to other groups. This is associated with lowest breast cancer risk among all the groups despite that this group has a higher incidence of breast cancer family history.18Of note, the proportion of hyperlipidemia is low in the control. This is largely due to removal of statin treatment group from the control. In addition, only 38% of patients in statins group have a diagnosis of hyperlipidemia, this is because statins are not only indicated for hyperlipidemia situation, but also recommended to optimize lipid levels in diabetes even if those patients may not qualify for the diagnosis of hyperlipidemia.The numbers of missing data vary among categories. Alcohol ever use category has the highest frequency of missing data (up to 25%). Nonetheless, there is no significant difference of missing data among the four medication groups and control group. Missing data were excluded from analysis.Both denosumab and bisphosphonates are approved by FDA to treat bone metastatic solid tumors or hematopoietic tumor myeloma involving bone. Those clinical scenarios are excluded from this study by excluding any patients with malignant diagnosis in first encounter, and any cancer diagnosis other than breast carcinoma during follow-up, and applying at least 365-day waiting time in medication groups for breast cancer case counting .9; others said that deduction was not duration dependent6; some indicated that it was present only among women with <2 years of use12; others suggested that it was more marked with increasing duration of use.8 The only denosumab and breast cancer association report studied women who filled a first prescription for denosumab (denosumab ever use).16 In our cohort, the average duration for both denosumab and bisphosphonates use is around 1–2 years and the dosage is shown in Denosumab is administrated subcutaneously every 6 months. Bisphosphonates are administered at variable interval of daily, weekly, quarterly, or yearly regime. The half life of bisphosphonates is up to years and denosumab still has a detectable serum level 9 months or later. The optimal duration of antiosteoporosis treatment has not been established. On the contrary, the reported timing of bisphosphonates use associated with breast cancer reduction has a wide variation: some found that the effect existed only after at least 1 yearHormone treatment is required for menopausal symptom control in some patients due to decreased endogenous estrogen level. The hormone treatment may indicate both decreased risk for breast cancer (lower endogenous hormone level) and increased risk . Hormone users are a highly selected group. We therefore separate this group from our control.19 Smoking might have an initiation role in breast cancer, although no causal relationship is suggested.2 Moreover, diabetes status, which has not been mentioned as a risk factor for breast cancer in World Health Organization (WHO) Classification of Tumors of the Breast, has been reported to be associated with breast cancer.21 We included those in our covariate analysis. We compared parameters of BP and lipidemia, which are related to general health and physical activity. The covariate analysis showed that there is no significant biomedical difference between the denosumab and bisphosphonates ever use groups.Well-accepted breast cancer risks include age, family history, imbalanced estrogen level, adiposity (BMI), and alcohol ever use.6–8 and two cohort studies11 suggest protective role of bisphosphonates toward breast cancer, and the other four studies12–14 did not prove significant protective effect, although no adverse effect is identified. The pooled results of those data15 showed that bisphosphonates were associated with 12% decrease risk of primary breast cancer . Our study favors an association of significantly decreased breast cancer risk with bisphosphonates use.There were nine large studies evaluating bisphosphonates use and primary breast cancer risk in different geographic area and in various populations before this study. Three case control studies10 observed a decrease in breast cancer risk associated with bisphosphonates use restricted to the year after treatment initiation . This is close to our finding which also showed breast cancer RR 0.37 (95% CI: 0.21–0.66) in bisphosphonates ever use patients. Per meta-analysis,15 the observed association of primary breast cancer risk with long-term use (≥1 year) of bisphosphonates seemed to be more robust and stronger than that of short-term use (<1 year) . However, the only randomized control trials showed that 3–4 years of bisphosphonate treatment did not decrease the risk of invasive breast carcinoma in postmenopausal women.14 It is noted that this randomized control study was not initially designed to study breast cancer outcome. Future large randomized control studies are required to verify this concern.The most recent large French cohort study16 There was no relationship between increasing number of denosumab doses and breast cancer risk (p-trend = 0.15).16 Our cohort study, which has a similar length of follow-up to the former study but with a bisphosphonates and denosumab comedication rate of 2.8% (84/3020 = 2.8%), did not come to the same conclusion. We showed that breast cancer risk in denosumab users is not significantly different from the control, although our study demonstrated association of lower breast cancer risk with bisphosphonates.Different from bisphosphonates whose cancer association has been studied for a decade, there is only one article recently published addressing the relationship between denosumab and breast cancer risk. This first case-control study showed that in a cohort of older women previously treated with bisphosphonates, denosumab use was associated with a 13% decreased breast cancer risk .17 It showed no associated risk of breast invasive carcinoma in statins users, but the comedication analysis did not include bisphosphonates use. All the cohort and case-control studies, which focused on the relationship of bisphosphonates and breast cancer, did not separate statins use from control group either.6–14 In our study, statins are associated with similar breast cancer protective effect as bisphosphonates. This is in consistence with published preclinical research.22–24 It is possible that the comparable breast cancer protective effect of bisphosphonates or statins might be masked when the control group has comedication of either of these two drugs.The initial epidemiological study on statins and breast cancer association is from the NHS cohort.We also showed that comedication of denosumab and statins is associated with lower cancer risk compared to denosumab ever use group, although the cancer cases (events) are less than 5, and statistical significance is hard to evaluate . Plans a2 In a contemporary observational cohort study, more than 100,000 women aged 50 to 71 were followed prospectively for 15 years. It showed that long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.19This healthier biomedical status in the hormone group  may explain the lowest breast cancer risk among all the groups, despite this group has a higher incidence of breast cancer family history. The absence of increased breast cancer risk may also be related to low dose and formulation of supplementary hormone in this group of patients. There is a great discrepancy on breast cancer risk and postmenopausal hormone use.3Bisphosphonates and denosumab are both antiresorption drugs inhibiting the osteoclasts activity, but with different binding sites in the bone. Bisphosphonates bind to bone mineral matrix hydroxyapatite at the surface of bone and especially within the resorption lacunae, occupying the site of resorption performed by activated osteoclasts, where they could be internalized by the active osteoclasts and inhibit the intracellular mevalonate pathway, leading to impaired function and apoptosis of osteoclasts. Denosumab is a newer monoclonal antibody first approved by FDA for treatment of postmenopausal osteoporosis in June 2010. It suppresses bone resorption by binding to receptor activator of nuclear factor kappa-B ligand (RANKL), preventing it from binding to its receptor on cell surfaces of not only osteoclasts but also osteoclasts precursors and decreasing osteoclast formation, activity, and survival.25 ERRα plays roles in osteoporosis and breast cancer development. ERRα transcriptional activity is enhanced by cholesterol and suppressed by statins and bisphosphonates.22 Meanwhile, the epigenetic impacts of statin and bisphosphonates on DNA methylation, histone deacetylation, and microRNAs occurring in normal cells could be both cancer preventing and promoting.23 RANKL/RANK/OPG system (receptor activator of nuclear factor/RANK ligand/osteoprotegerin) is not only critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, but also can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression.24 The regulatory network is summarized in The pharmaceutical effects of bisphosphonates are mediated by estrogen related receptor α (ERRα).The preclinical studies suggest possible protective role of bisphosphonates on breast cancer. The preclinical studies also suggest a potential synergistic effect between denosumab and statins on breast cancer reduction as well.One might speculate that the antiosteoporosis medication group might have lower estrogen level than control. One of the factors leading to osteoporosis is plummet of estrogen at age 50 years and older. The estrogen level is mostly affected by age and positively related to BMI or obesity. Those two factors show no significant difference between the antiosteoporosis medication and control groups in our study. These may partially solve the indication bias concern. Preclinical studies , N (nodes), M (metastasis), and biological types, including estrogen/progesterone receptor, and HER2  status according to American Joint Committee on Cancer (AJCC) 8th edition.This is the first study to compare the risk of primary breast cancer between bisphosphonates and denosumab users head-to-head. The results, if supported by further studies could be potentially helpful for clinical decision when breast cancer is a concern and patients are treated for osteoporosis with or without comorbidity of hyperlipidemia.Our data support an association of lower breast cancer risk with bisphosphonates use in elderly women. We did not observe a lower breast cancer risk in denosumab group; however, our data revealed a potential lower breast cancer risk in denosumab users with concurrent statins use and this requires further study.The data of this study are available from the Clinical and Translational Science Institute, UCLA. HIPPA restrictions apply.This study was approved by the Research Ethics Board of University of California at Los Angeles.