Performance of FRAX in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study

FRAX was developed to predict 10-year probability of major osteoporotic fracture (MOF) and hip fracture in the general population. Aromatase inhibitors (AI) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk. AI exposure is not a direct input to FRAX but is captured under “secondary osteoporosis”. To inform use of FRAX in women treated with AI, we used a population-based registry for the Province of Manitoba, Canada, to identify women aged ≥40 years initiating AI for breast cancer with at least 12 months’ AI exposure (n = 1775), women with breast cancer not receiving AI (n = 1016), and women from the general population (n = 34,205). Among AI users, fracture probability estimated without BMD (AI use coded as secondary osteoporosis) significantly overestimated risk (10-year observed/predicted ratio 0.56, 95% confidence interval [CI] 0.45–0.68; 10-year hip fracture observed/predicted ratio 0.33, 95% CI 0.18–0.49). However, when BMD was included in the fracture probability, there was no significant difference between observed and predicted fracture risk. In Cox proportional hazards models, FRAX stratified risk of MOF, hip, and any fracture equally well in all subgroups (p-interaction >0.1). When adjusted for FRAX score without BMD, with AI use coded as secondary osteoporosis, AI users were at significantly lower risk for MOF (hazard ratio [HR] = 0.78, 95% CI 0.64–0.95), hip fracture (HR = 0.46, 95% CI 0.29–0.73) and any fracture (HR = 0.75, 95% CI 0.63–0.89). AI use was no longer significantly associated with fractures when AI use was not entered as secondary osteoporosis in FRAX without BMD or when BMD was included in the FRAX calculation. In conclusion, FRAX scores stratify fracture risk equally well in women receiving AI therapy as in non-users, but including secondary osteoporosis as a risk factor for AI users overestimates fracture risk. Our results call this practice into question. © 2019 American Society for Bone and Mineral Research.     

芳香化酶抑制剂对绝经后乳腺癌患者 骨折的影响

目的探讨芳香化酶抑制剂(aromatase inhibitors,AI)对绝经后乳腺癌患者骨折发生的影响。方法选择接受AI治疗的绝经后乳腺癌患者70例为治疗组,未接受任何内分泌治疗的绝经后乳腺癌患者89例为对照组。收集骨折相关资料,并以5年用药期为界,比较两组患者骨折发生率及风险。同时,在治疗组患者中,分析相关临床风险因素对骨折发生的影响。结果治疗组和对照组患者总骨折发生率分别为12.86%(9/70)和1.12%(1/89),5年用药期间的骨折发生率分别为10.00%(7/70)和1.12%(1/89),5年用药期过后,治疗组8例患者中有2例发生骨折,而对照组19例患者无一例发生骨折。治疗组患者的骨折发生率均高于对照组(P=0.003,0.018,0.026)。治疗组患者总骨折发生风险和5年用药期间的骨折发生风险高于对照组(P=0.008,0.026)。治疗组患者中,个人骨折史和骨折家族史是增加骨折发生的临床风险因素。结论接受AI治疗的绝经后乳腺癌患者的骨折发生率和骨折发生风险明显增加。因此,绝经后乳腺癌患者在使用AI防治乳腺癌时,要全面评估骨折发生的风险,必要时应采取有效的临床干预措施。     

乳腺癌芳香化酶抑制剂治疗期间骨丢失的长期随访结果

目的 评估绝经后激素受体阳性早期乳腺癌患者术后5年芳香化酶抑制剂（aromatase inhibitor,AI）辅助内分泌治疗过程中的骨丢失情况,为骨健康管理提供依据。方法 本研究为前瞻性观察性研究,入组绝经后激素受体阳性早期乳腺癌患者,接受股骨颈、全髋和腰椎L1-L4等部位的双能X线骨密度检测。AI辅助内分泌治疗前进行基线骨密度检查,治疗期间每年检查骨密度1次。分析AI治疗过程中骨密度变化以及骨质疏松发生率。结果 2013年11月至2016年8月共纳入131例患者,中位年龄60岁,中位绝经年龄50岁,AI治疗时间60～100个月。中位随访86个月,AI治疗5年期间患者腰椎、股骨颈、全髋骨密度逐年下降,5年骨密度总下降率分别为6.90%、5.68%、7.14%,其中第1年骨密度下降最快,第2～5年骨密度平稳下降。腰椎骨密度第1年变化率显著高于第2～5年骨密度变化率（P＜0.01）。进一步分层分析显示,基线骨密度、年龄以及体质量指数值未影响患者骨密度下降率。5年间共17例（17%）患者新发骨质疏松,其中15例为基线骨量低下患者,76%出现在腰椎（13/17）,骨折发生率2%（2/100）。结论 绝经后早期乳腺癌患者5年AI辅助内分泌治疗期间骨密度呈持续下降趋势。应加强AI治疗期间的骨健康管理,早期干预减少骨质疏松的发生。     

Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper

Summary

Aromatase inhibitors (AIs) are widely used in women with breast cancer, but they are known to increase bone loss and risk of fractures. Based on available evidence and recommendations, an ESCEO working group proposes specific guidance for the prevention of AIs-induced bone loss and fragility fractures.

Introduction

Aromatase inhibitors (AIs) are now the standard treatment for hormone receptor-positive breast cancer. However, deleterious effects of AIs on bone health have been reported. An ESCEO working group proposes guidance for the prevention of bone loss and fragility fractures in post-menopausal women with breast cancer receiving AIs.

Methods

A panel of experts addressed the issue of skeletal effects of AIs and effectiveness of antifracture therapies for the prevention of AI-induced bone loss and fractures. Recommendations by national and international organizations, and experts’ opinions on this topic were evaluated.

Results

All aromatase inhibitors are associated with negative effects on the skeleton, resulting in bone loss and increased risk of fragility fractures. Current guidelines suggest approaches that differ both in terms of drugs proposed for fracture prevention and duration of treatment.

Conclusion

The ESCEO working group recommends that all AI-treated women should be evaluated for fracture risk. Besides general recommendations, zoledronic acid 4?mg i.v. every 6?months, denosumab s.c., or possibly oral bisphosphonates should be administered for the entire period of AI treatment to all osteoporotic women (T-score hip/spine <?2.5 or ≥1 prevalent fragility fracture), to women aged ≥75 irrespective of BMD, and to patients with T-score <?1.5?+?≥1 clinical risk factor or T-score <?1.0?+?≥2 clinical risk factors. Alternatively, therapy could be considered in patients with a FRAX-determined 10-year hip fracture probability ≥3%.     

Improving bone health in patients with early breast cancer by adding bisphosphonates to letrozole: the Z-ZO-E-ZO-FAST program

Women undergoing treatment for breast cancer often have a number of pre-existing risk factors for bone loss, including existing or induced postmenopausal status. Long-term anticancer treatments may further augment this risk, inducing further bone-loss, increasing the incidence of bone fractures, associated morbidity and mortality, and healthcare costs. Long-term treatment with third-generation antiaromatase agents (AAAs) is used more and more instead of or after the selective estrogen-receptor modulator tamoxifen for the adjuvant treatment of postmenopausal women with breast cancer. These AAAs include anastrozole, letrozole, and exemestane, and all are superior to tamoxifen in both efficacy and safety. In particular, they reduce the incidence of serious adverse events such as thromboembolism and endometrial cancer that are associated with tamoxifen treatment. On the other hand, the AAAs lead to profound estrogen depletion and appear to have a pronounced effect on bone mineral density (BMD), and a significantly higher incidence of osteoporosis/osteopenia and bone fracture has been reported in some trials. Bisphosphonate therapies, including zoledronic acid (ZA), have emerged as a promising means of reducing bone loss associated with antiaromatase therapy. Several large, randomized, multicenter trials are underway to determine whether upfront or delayed ZA therapy can decrease BMD losses in patients undergoing treatment with the antiaromatase agent letrozole (Z-FAST; ZO-FAST, and E-ZO-FAST), and early results from the Zometa-Femara adjuvant synergy trial (Z-FAST) trial indicate a significant benefit of upfront ZA therapy compared with delayed ZA therapy. Forthcoming results from all these trials should determine whether ZA could be used to improve bone heath in women undergoing adjuvant therapy with AAAs for breast cancer.     

The role of bisphosphonates in preventing skeletal complications of hormonal therapy

Androgen deprivation therapy (ADT) is associated with a significant decrease in bone mineral density (BMD), and continued exposure seems to increase the risk of osteoporotic fracture in men who have prostate cancer treated with this strategy. Men who have prostate cancer may have low BMD before initiation of ADT. Bisphosphonates are pyrophosphate analogs that decrease bone resorption primarily through direct inhibition of osteoclast activity and proliferation. Several bisphosphonates have been evaluated in randomized clinical trials, and the cumulative data show that these medications increase or maintain BMD in men receiving ADT for prostate cancer. The effect on clinical fractures has not been assessed adequately, but bisphosphonates offer an important potential treatment modality to reduce the risk of osteoporotic fracture in this population of men.     

A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats

Recent evidence has demonstrated that long-term estrogen deprivation using aromatase inhibitor therapy in postmenopausal women with breast cancer results in bone loss and increased fracture risk. Bisphosphonates are potent inhibitors of bone resorption and have demonstrated efficacy in preventing bone loss in postmenopausal women with low bone mineral density (BMD) and in patients with breast cancer receiving estrogen deprivation therapy. Therefore, this study investigated the effects of the bisphosphonate zoledronic acid on BMD and bone strength in rats treated with the aromatase inhibitor, letrozole. Peripheral quantitative computed tomography demonstrated that treatment of rats with daily oral letrozole (1 mg/kg) induced significant bone loss and cortical thinning compared with control animals (P < 0.01). A single prior intravenous dose of zoledronic acid dose dependently protected against letrozole-induced bone loss and cortical thinning, with the highest evaluated dose (20 microg/kg) resulting in BMD values that were not significantly different from controls over the 24 weeks of letrozole treatment. Furthermore, biomechanical testing of the distal femoral metaphysis demonstrated that zoledronic acid (20 microg/kg) significantly prevented the decrease in stiffness and elastic modulus induced by letrozole treatment. Taken together, these data support the use of zoledronic acid for the prevention of bone loss in women with breast cancer receiving aromatase inhibitor therapy.     

Incidence and risk factors for low trauma fractures in men with prostate cancer

BACKGROUND: Men with prostate cancer on androgen deprivation therapy (ADT) are at increased risk of bone loss. The present study sought to determine the incidence of low trauma fracture in men with prostate cancer (PC), and to characterize the association between potential risk factors and fracture risk in these men. METHODS: In the prospective, population-based Dubbo Osteoporosis Epidemiology Study, 43 men aged 60+ years reported a history of prostate cancer; among whom, 22 men received ADT, and 21 men did not. Low-trauma fractures were ascertained between 1989 and 2004. Bone mineral density at the femoral neck (FNBMD), postural instability and lifestyle factors were obtained at baseline. RESULTS: Men with prostate cancer had significantly higher lumbar spine BMD than those without cancer (p=0.013). During the follow-up period, 15 men with prostate cancer had sustained a fracture, yielding the age-adjusted incidence of fracture among this group was 31.6 per 1000 person-years, which was greater than those without cancer (22.1 per 1000 person-years). The age-adjusted incidence of fracture was more pronounced among those with prostate cancer on ADT (40.2 per 1000 person-years). After adjusting for age, the increase in fracture risk among prostate cancer patients was associated with lower femoral neck BMD (hazard ratio [HR] per SD=1.8, 95% CI: 1.0-3.4) and increased rate of bone loss (HR 2.3, 1.2-4.6). CONCLUSIONS: Men with prostate cancer, particularly those treated with ADT, had an increased fracture risk. Although the average BMD in men with prostate cancer was higher than men without cancer, a low BMD prior to treatment or increased rate of bone loss after initiating ADT treatment was each a significant predictor of fracture in these.     

Clinical risk factor status in patients with vertebral fracture but normal bone mineral density

BACKGROUND CONTEXTNormal bone mineral density (BMD) as measured by dual-energy x-ray absorptiometry (DXA) is present in approximately 10% of older adults with fracture. BMD alone does not evaluate bone quality or clinical risk factors, and therefore, may not adequately capture a patient's fracture risk. Thus, despite a normal DXA-measured BMD, the underlying bone may be abnormal, suggesting that further bone health evaluation, and potentially, pharmacologic treatment may be warranted.PURPOSETo determine the prevalence of normal BMD, clinical fracture risk factors, and quantitative risk of fracture using the Fracture Risk Assessment Tool (FRAX) in vertebral fracture patients with normal BMD enrolled in the Own the Bone registry, thus facilitating identification of those who meet criteria for anti-osteoporosis therapy.STUDY DESIGN/SETTINGRetrospective, national registry-based cohort.PATIENT SAMPLEFrom July 2016 to July 2021, 1,807 patients age ≥50 who sustained a vertebral fracture and had DXA data available from within 2 years prior to enrollment in the American Orthopaedic Association's Own the Bone (AOA OTB) registry were included.OUTCOME MEASURESWorld Health Organization (WHO) DXA T-score based bone classification criteria; FRAX risk scores of major osteoporotic fracture or hip fracture.METHODSDemographic data, prior fracture site, and clinical fracture risk factors were collected. BMD status was classified by the WHO T-score criteria: ≥ -1.0 normal, -1.1 to -2.4 osteopenia, and ≤ -2.5 osteoporosis, with low bone mass including either osteopenia or osteoporosis. In normal BMD patients, FRAX scores were calculated with and without BMD, with the treatment threshold defined as a major osteoporotic fracture risk ≥20% or hip fracture risk ≥3%.RESULTSMean±SD age was 72.0±9.7, 78.1% were female, and 92.4% were Caucasian. Normal BMD was present in 7.9%. Clinical fracture risk factors including alcohol use ≥3 units/day and history of ≥2 falls in the year prior to enrollment were more common in normal BMD (11.2% and 28%, respectively) compared to low bone mass patients (3.4% and 25.2%, respectively). A prior vertebral fracture had occurred in 49.5% with normal BMD compared to 45.8% with low bone mass, while a prior non-major osteoporotic fracture occurred in 28.9% and 29.3% of normal BMD and low bone mass patients, respectively. In normal BMD patients, either a prior fracture or FRAX risk with BMD meeting treatment thresholds was present in 85%.CONCLUSIONSClear indications for receipt of pharmacologic therapy, ie, prior fracture or elevated fracture risk, were present in most patients with vertebral fracture and normal BMD enrolled in the AOA OTB. Prior non-major osteoporotic fractures were common and may be useful indicators of underlying bone disease. Surgeons must recognize that other important risk factors apart from BMD may indicate poor bone health, and thus, help guide further bone health evaluation.     

Bone loss and the evolving role of bisphosphonate therapy in prostate cancer

Androgen deprivation therapy (ADT) can result in significant loss of bone mineral density (BMD) but to date, there are no prospective studies that document the true severity of bone loss and resulting fracture rates. In the general population, however, the incidence of low BMD is increasing in elderly men. Men suffer more morbidity and mortality from fractures associated with low BMD than women. Problems of underdiagnosis and undertreatment in men can be addressed with enhanced awareness of the risk factors for bone loss in men and the available treatment options. Guidelines for diagnosis of low BMD in women can probably be applied to men. Treatment options have not been studied as extensively in men. For men treated with ADT for prostate cancer, however, use of intravenous zoledronic acid at the initiation of ADT has been shown to prevent and even reverse bone loss. Although the routine use of bisphosphonates to prevent bone loss is not yet recommended, zoledronic acid is a logical choice of therapy in men who have low BMD at baseline or who develop bone loss during the course of therapy. In addition to its effects on BMD, zoledronic acid has also been shown to decrease skeletal morbidity in men with metastatic hormone-refractory prostate cancer. Whether zoledronic acid or other bisphosphonates might actually prevent or delay the development of bone metastases remains to be studied in randomized clinical trials.     

Management of cancer treatment-induced bone loss in early breast and prostate cancer - a consensus paper of the Belgian Bone Club

Cancer treatment-induced bone loss (CTIBL) is one of the most important side effects of adjuvant antineoplastic treatment in hormone-dependent neoplasms. Chemotherapy, GnRH analogs and tamoxifen can induce marked bone loss in premenopausal women with early breast cancer. Aromatase inhibitors (AIs) are replacing tamoxifen as the preferred treatment for postmenopausal women. As a class effect, steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs increase bone turnover and cause bone loss (4%-5% over 2 years). When compared to tamoxifen, the risk of getting a clinical fracture under AI treatment is increased by 35%-50%. In patients with prostate cancer, androgen deprivation therapy (ADT) increases bone turnover, reduces bone mass (4%-5% per year) and increases the fracture rate depending on the duration of therapy. Zoledronic acid can prevent accelerated bone loss induced by goserelin in premenopausal women, by letrozole in postmenopausal women and by ADT in men. More limited data indicate that weekly alendronate or risedronate could also be effective for preventing CTIBL. Initiation of therapy early, prior to the occurrence of severe osteoporosis, rather than after, may be more effective. Bisphosphonate treatment should be considered in osteoporotic but also in osteopenic patients if other risk factor(s) for fractures are present.     

Risk factors for low BMD in healthy men age 50 years or older: a systematic review

Summary  In this systematic review, we summarize risk factors for low bone mineral density and bone loss in healthy men age 50 years or older. Consistent risk factors were: age, smoking, low weight, physical/functional limitations, and previous fracture. Data specific to men has clinical and policy implications. Introduction  Osteoporosis is a significant health care problem in men as well as women, yet the majority of evidence on diagnosis and management of osteoporosis is focused on postmenopausal women. The objective of this systematic review is to examine risk factors for low bone mineral density (BMD) and bone loss in healthy men age 50 years or older. Materials and methods  A systematic search for observational studies was conducted in MEDLINE, Cochrane Database of Systematic Reviews, DARE, CENTRAL, CINAHL and Embase, Health STAR. The three main search concepts were bone density, densitometry, and risk factors. Trained reviewers assessed articles using a priori criteria. Results  Of 642 screened abstracts, 299 articles required a full review, and 25 remained in the final assessment. Consistent risk factors for low BMD/bone loss were: advancing age, smoking, and low weight/weight loss. Although less evidence was available, physical/functional limitations and prevalent fracture (after age 50) were also associated with low BMD/bone loss. The evidence was inconsistent or weak for physical activity, alcohol consumption, calcium intake, muscle strength, family history of fracture/osteoporosis, and height/height loss. Conclusion  In this systematic review, we identified several risk factors for low BMD/bone loss in men that are measurable in primary practice. For the Male BMD Guidelines Committee of Osteoporosis Canada     

Aromatase Inhibitor Adjuvant Chemotherapy of Breast Cancer Results in Cancer Therapy Induced Bone Loss

Aromatase Inhibitors are anti-estrogen agents that have proven efficacy for adjuvant therapy of estrogen receptor positive breast cancer primarily in post menopausal women with estrogen receptor positive breast cancer but increase the risk of cancer therapy induced bone loss (CTIBL). Recent studies have shown the potential benefit of bisphosphonate therapy to play a dual role in the management of breast cancer. These studies provide evidence that bisphosphonate therapy in conjunction with aromatase inhibitors (AI), not only decreases the risk of osteoporosis but, in addition, may improve survival from breast cancer.     

Treatment of premenopausal women with low bone mineral density

Interpretation of bone mineral density (BMD) results in premenopausal women is particularly challenging, because the relationship between BMD and fracture risk is not the same as for postmenopausal women. Z scores rather than T scores should be used to define “low BMD” in premenopausal women. The finding of low BMD in a premenopausal woman should prompt an evaluation for secondary causes of bone loss. If a secondary cause is found, management should focus on treatment of this condition. In some cases in which the secondary cause cannot be addressed, such as glucocorticoid therapy or cancer chemotherapy, treatment with a bone-active agent to prevent bone loss should be considered. In women with no fractures and no known secondary cause, low BMD may not signify compromised bone strength. BMD is likely to remain stable in these women, and pharmacologic therapy is rarely justified. Assessment of markers of bone turnover and follow-up bone density measurements can help to identify those with an ongoing process of bone loss that may indicate a higher risk for fracture, and possible need for pharmacologic intervention.     

应用FRAX评价乳腺癌术后患者骨折风险的临床研究

目的应用骨折风险评估工具(fracture risk assessment tool,FRAX)评价乳腺癌术后患者骨折风险的临床研究。方法选取2017年3月至2019年8月在连云港市第一人民医院接受过手术治疗的Ⅰ期至Ⅲ期乳腺癌女性181例作为观察组,并选取181例年龄和身体质量指数匹配的非乳腺癌女性作为对照组,收集个人基本信息、骨折风险因素、股骨颈骨密度(bone mineral density,BMD)及治疗方式等资料,比较不同组间的骨折风险,并进行骨折风险与临床因素的回归分析。结果(1)乳腺癌术后患者10年内主要部位骨质疏松性骨折概率(probability of major osteoporotic fracture,PMOF)和10年内髋部骨折概率(probability of hip fracture,PHF)较对照组无显著增加(P=0.570、0.582);(2)PMOF在芳香化酶抑制剂组最高,他莫昔芬组最低(P<0.05)。芳香化酶抑制剂组的PHF显著高于单纯化疗组和他莫昔芬组(P<0.05);(3)回归分析显示,年龄、股骨颈BMD、骨折史、父母髋部骨折史和激素应用史对PMOF的影响具有统计学意义(P<0.05)。年龄、股骨颈BMD、骨折史对PHF的影响具有统计学意义(P<0.05)。结论应用FRAX工具评估乳腺癌术后患者的骨折风险尚需进一步研究。     

The epidemiology of quantitative ultrasound: A review of the relationships with bone mass, osteoporosis and fracture risk

Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.     

Osteoporosis and hormone replacement therapy

Hormone replacement therapy prevents bone loss and the increase in bone resorption due to the hormone deficiency in oestrogen in postmenopausal women. The WHI (Women's Health Initiative) randomised, double-blind study against placebo, demonstrated that which all the epidemiological trials had already suggested: replacement therapy can reducing by around 30% the risk of fractures in postmenopausal women. Administration of hormone replacement therapy requires account being taken of (in view of the uncertainties regarding the anti-fracture effect of low dose therapy): the duration (in view of the absence of remnant effect of the product on bone loss and on the risk of fracture) and the benefit/risk ration (in view of the benefits demonstrated on climacteric disorders, but the increase in risk of breast cancer). The menopause is the occasion to assess individual risks, notably vascular and of fractures, taking into account the clinical risk factors and measurement of bone density.     

Devising global strategies for fracture-risk evaluation

Fracture prevention is the goal of osteoporosis treatment. Bone mineral density (BMD) has been the main criterion for deciding whether to initiate treatment, which is usually recommended when the BMD is less than -2.5 SDs from the mean in young women. However, the need to base treatment decisions on the overall fracture risk, rather than on BMD values alone, is now increasingly recognized. Several factors predict the fracture risk independently from BMD. Combining these factors to BMD may improve patient selection for osteoporosis therapy. In addition to low BMD values, factors associated with a high fracture risk include advanced age, prior fractures in the patient or family, low body mass index, smoking, glucocorticoid therapy, unfavorable profile of bone turnover markers, and risk factors for falls. There is no consensus yet about the best strategy for using these risk factors to assist in treatment decisions. A collaborative center set up by the World Health Organization is evaluating pooled data from prospective studies in order to better define high-risk patient subsets that are likely to benefit from osteoporosis treatment to prevent fractures. The results will serve to develop clinical guidelines for identifying high-risk patients.     

Fracture risk in women with breast cancer: a population-based study

A positive association has been reported between greater bone density and higher breast cancer risk, suggesting that these women could be at reduced risk of fracture. To estimate fracture risk among unselected community women with breast cancer and to systematically assess associations with various risk factors including breast cancer treatments, we conducted a population‐based historical cohort study of 608 Olmsted County, MN, USA, women with invasive breast cancer first diagnosed in 1990 to 1999 (mean age 61.6 ± 14.8 years), who were followed for 5776 person‐years. Altogether, 568 fractures were observed in 270 women (98 per 1000 person‐years). Overall fracture risk was elevated 1.8‐fold, but the absolute increase in risk was only 9%, and 56% of the women did not experience a fracture during follow‐up. Excluding pathologic fractures (15%) and those found incidentally (24%), to allow for ascertainment bias, the standardized incidence ratio was 1.2 (95% confidence interval [CI] 0.99 to 1.3) for total fracture risk and 0.9 (95% CI 0.7 to 1.2) for osteoporotic fracture risk alone. Various breast cancer treatments were associated with an increased risk of fracture, but those associations were strongest for pathologic fractures, which were relatively more common among the women who were premenopausal when their breast cancer was diagnosed. Moreover, underlying clinical characteristics prompting different treatments may have been partially responsible for the associated fracture outcomes (indication bias). These data thus demonstrate that breast cancer patients in general are not at greatly increased risk of fracture but neither are they protected from fractures despite any determinants that breast cancer and high bone density may have in common. © 2012 American Society for Bone and Mineral Research.