Increased fracture rate in women with breast cancer: a review of the hidden risk
© Body; licensee BioMed Central Ltd. 2011
Received: 7 April 2011
Accepted: 29 August 2011
Published: 29 August 2011
Women with breast cancer, particularly individuals diagnosed at a relatively early age, have an increased incidence of fractures. Fractures can have serious clinical consequences including the need for major surgery, increased morbidity and mortality, increased cost of disease management, and reduced quality of life for patients. The primary cause of the increased fracture risk appears to be an accelerated decrease in bone mineral density (BMD) resulting from the loss of estrogenic signaling that occurs with most treatments for breast cancer, including aromatase inhibitors. However, factors other than BMD levels alone may influence treatment decisions to reduce fracture risk in this setting. Our purpose is to review current evidence for BMD loss and fracture risk during treatment for breast cancer and discuss pharmacologic means to reduce this risk.
Fracture risk during treatment for breast cancer may be influenced by the rate of BMD loss and the consequent rapid alterations in bone microarchitecture, in addition to the established fracture risk factors in postmenopausal osteoporosis. The rapid decrease in BMD during adjuvant chemoendocrine therapy for breast cancer may necessitate more aggressive pharmacotherapy than is indicated for healthy postmenopausal women who develop osteoporosis. Over the last few years, clinical trials have established the effectiveness of bisphosphonates and other antiresorptive agents to preserve BMD during adjuvant therapy for early breast cancer. In addition, some bisphosphonates (eg, zoledronic acid) may also delay disease recurrence in women with hormone-responsive tumors, thereby providing an adjuvant benefit in addition to preserving BMD and potentially preventing fractures.
It is likely that a combined fracture risk assessment (eg, as in the WHO FRAX algorithm) will more accurately identify both women with postmenopausal osteoporosis and women with breast cancer who require bone-protective therapy.
Keywordsadjuvant therapy aromatase inhibitor bisphosphonate chemotherapy-induced menopause osteoporosis zoledronic acid
Incidence of Fractures in Women With Breast Cancer
Vertebral fracture incidence in women with breast cancer
Controlsa (n = 776)
Breast cancer, at diagnosis (n = 352)
Breast cancer, recurrentc (n = 82)
Follow-up, years ± SD
2.9 ± 0.3
2.1 ± 1.2
1.8 ± 1.4
Prevalence of vertebral fractures, %
Annual fracture incidence, %
Mean number of fracturesb
Mean severity scoreb
The increased risk of fracture in BC patients has become even more evident following the increased use of AIs as adjuvant therapy. Despite substantial improvements in disease-free survival compared with tamoxifen, both steroidal (eg, exemestane) and non-steroidal (eg, anastrozole and letrozole) AIs have been associated with rapid loss of BMD and increased fracture risk in clinical trials [5–7]. Although this increase in fracture risk appears to be reversible on discontinuation of AI treatment,[5, 6] it has now become evident that the rate of BMD loss during AI therapy far exceeds the BMD loss observed in postmenopausal osteoporosis (PMO), and is therefore likely to need proactive management to preserve BMD and prevent fractures.
Clinical Implications of Fractures
Osteoporosis is characterized by decreased bone strength and increased fracture risk (including hip and vertebral fractures), and is a significant health concern in the developed world. Hip fractures secondary to osteoporosis are associated with an approximately 2-fold increase in mortality during the 12 months following the fracture . Hip fractures result in prolonged hospitalization (an average of 16.3 days in an orthopedic ward and 63.6 days in a rehabilitation hospital in 1 study) and are associated with increased risks of deep vein thrombosis (DVT; reported in up to 31% of patients undergoing surgery for hip fractures), pulmonary emboli, and pressure ulcers [11–14]. Moreover, approximately 20% of patients discharged after successful surgery for hip fractures are referred back for in-patient hospital care with suspected DVT or pulmonary embolism within 3 months . Vertebral fractures can be associated with chronic pain and decreased pulmonary function .
Risk Factors for Fracture
Risk factors for development of fractures or bone mineral density lossa
Modifiable risk factors
Other risk factors
Excessive alcohol consumption
Existing low body mass index (< 20 kg/m2) and excessive weight loss
Low calcium or vitamin D intake
Use of medications affecting absorption of calcium
or absorption or production of vitamin Db
Use of corticosteroidsb
Use of medications decreasing the production of estrogen or testosteroneb
Low estrogen or testosterone levels
Low bone mass
Race (Asian, white)
Fracture history (personal, familial)b
Emphysema, chronic bronchitis
Aromatase inhibitors, used to suppress estrogen levels in postmenopausal women who have hormone receptor-positive BC, are also associated with rapid BMD loss and increased fracture risk. In long-term follow-up of phase III trials of AIs versus tamoxifen as adjuvant therapy for early stage BC, the incidence of fractures was reported to be 33% to 43% higher in AI-treated patients compared with tamoxifen [5–7]. This increase in fracture risk is maintained at least for the duration of AI therapy. The risk appears to wane after completion of treatment,[5, 6] but more robust off-treatment data are needed to confirm this observation. Overall, because AIs are now replacing tamoxifen as the treatment of choice for postmenopausal women with early stage BC, steps should be taken to identify patients at risk for fractures to ensure proper prophylactic treatment.
Steroids (which BC patients may have received previously or concurrently for pre-existing conditions, underlying symptoms, or control of emesis) can also increase fracture risk . In addition, postmenopausal women with BC may have fracture risk factors that are independent of their BC therapy, but nonetheless increase their fracture risk. Bone mineral density is an established key determinant of fracture risk and has been incorporated into many clinical guidelines for assessing fracture risk [27–29]. Osteoporosis is still defined on the basis of BMD measurement. Thus, the World Health Organization (WHO) defines osteopenia (BMD T-score < -1.0 and > -2.5) and osteoporosis (BMD T-score ≤ -2.5) relative to peak bone mass for premenopausal women and advocates bone-directed therapy for all women with osteoporosis. However, many risk factors that are independent of BMD (Table 2[4, 21]) also significantly increase fracture risk, including increasing age, low body mass index, personal or family history of fractures, and current or history of smoking [22, 30].
Mechanisms of Accelerated Bone Loss in Breast Cancer Differ From Postmenopausal Osteoporosis
The risk of fragility fractures increases progressively and continuously as BMD decreases . Several mechanisms contribute to bone loss in BC patients. Breast cancer itself, in the absence of bone metastases, might interfere directly with bone metabolism, for example increasing osteoclastic activity by stimulating the release of transforming growth factors . Bone loss can also arise because of low estrogen levels caused by chemotherapy-induced ovarian failure or ovarian function suppression in premenopausal women [25, 32]. In addition, AI therapy to suppress peripheral estrogen production in postmenopausal women can exacerbate age- and menopause-related BMD loss [5–7, 17, 33]. In general, decreased estrogen levels are associated with increased fracture risk (Figure 2) regardless of the mechanism underlying such hypogonadism .
Bone loss associated with BC treatment is substantially more rapid than during natural menopause. Women undergo an accelerated, transient phase of bone loss during natural menopause (~3% per year during the first 1-2 years, slowing to approximately 1% annually thereafter) . In contrast, surgically induced menopause (oophorectomy) causes a larger reduction of total bone mass of up to 20% within 18 months in some studies, and BMD appears to continue decreasing thereafter . Similarly, ovarian suppression with goserelin in premenopausal women can decrease BMD by 6% to 10% within the first 2 years . The effect of goserelin-induced ovarian suppression in combination with AIs in this population is even more severe, with reports of up to 17.3% BMD loss within 3 years compared with baseline (P < .0001) in 1 study . The rate of bone loss is also marked in postmenopausal women undergoing treatment with AIs, which block conversion of androgens to estrone and estradiol, thereby effectively eliminating estrogenic signaling . This AI-associated bone loss (AIBL) continues throughout the duration of therapy, and averages approximately 2% per year [8, 38]. The negative effect of estrogen depletion on bone appears to be associated with all AIs [17, 33]. This class effect highlights the necessity to monitor bone loss and fracture risk in all patients receiving AI therapy, and suggests that pharmacotherapy may be needed in some patients to prevent bone loss and reduce fracture risk.
Several clinical trials have investigated bisphosphonates and other antiresorptive agents for the prevention of AIBL in nonosteoporotic patients. These include studies of oral ibandronate (Arimidex® Bondronat®; ARIBON), risedronate (Study of Anastrozole with the Bisphosphonate RisedronatE; SABRE), denosumab (Hormone Ablation Therapy in Breast Cancer; HALT-BC), and 4 independent trials of intravenous zoledronic acid: 1 in premenopausal (ABCSG-12) and 3 in postmenopausal women (Zometa/Femara Adjuvant Synergy Trials; Z-FAST, ZO-FAST, E-ZO-FAST) [42–44]. Results from these trials demonstrate that upfront bone-directed therapy effectively prevents bone loss and maintains or increases BMD in women receiving AIs or other endocrine therapy for early BC. In addition, it has been shown that the addition of zoledronic acid to adjuvant endocrine therapy may also improve clinical outcomes (ie, delay disease recurrence in bone and other sites) compared with endocrine therapy alone in pre- and postmenopausal women with early stage hormone-responsive BC [44–46].
Monitoring Fracture Risk
Estimation of fracture risk in women with breast cancer has a further level of complexity in that the disease and its treatment can, in themselves, alter BMD (and. therefore, fracture risk). The FRAX tool has some inherent limitations when applied to patients with breast cancer--because this tool has been validated using population-based studies in generally healthy postmenopausal women, it might not take factors specific to breast cancer (eg, the rate of bone loss, the effect of anticancer therapies that cause hypogonadism) into sufficient account . Furthermore, FRAX does not adjust for a "dose-response" in fracture risk factors; this might be especially relevant in the breast cancer setting, wherein long-term treatment with AIs as well as other causes of bone loss would be included under the single "secondary osteoporosis" feature in the FRAX tool, thereby resulting in underestimation of the net increase in fracture risk. The duration of AI therapy is also not taken into account. Nonetheless, the FRAX index assesses fracture risk using a comprehensive list of clinical and individual risk factors, and can be used to compute long-term fracture risk even in the absence of BMD measurements . Although some guidelines (eg, American Society of Clinical Oncology [ASCO] guidelines) continue to recommend thresholds for bone-directed therapy based primarily on BMD, the last 2 to 3 years have witnessed a growing awareness of fracture risk factors beyond BMD T-scores.
Recent clinical guidelines have already begun to include fracture risk factors for patient assessment and treatment decisions,[22, 30, 51] and have even attempted to refine the FRAX approach specifically for the breast cancer setting by using a similar combination of fracture risk factors, but with more well-defined criteria (instead of yes/no) in an attempt to address the unique bone health challenges posed by adjuvant endocrine therapy. In a recent consensus statement from an international panel of bone health experts, periodic monitoring of BMD levels is recommended for all women with breast cancer receiving AI therapy, and pharmacologic intervention is suggested for patients with normal T-scores or mild osteopenia if they experience an annual BMD decrease of 10% or more compared with pretreatment levels . Moreover, this treatment algorithm recommends bone-directed therapy regardless of baseline BMD for women with multiple fracture risk factors (≥ 2 predefined fracture risk factors similar to those described in Table 2) . The most comprehensive fracture risk assessment algorithm for patients with early breast cancer is described in a position statement from an expert panel in the United Kingdom . This algorithm classifies patients into low-, intermediate-, and high-risk groups for fracture based on hormonal status (eg, premature menopause/use of AIs), fracture history, secondary osteoporosis, and BMD changes during adjuvant therapy for breast cancer . Such algorithms for fracture risk assessment specifically in the breast cancer setting should help guide treatment decisions to preserve bone health in such patients.
It is likely that a combined fracture risk assessment will more accurately identify both women with PMO and women with BC who require bone-protective therapy; moreover, treatment options (ie, drug choice, dose, and frequency) should probably be influenced by the severity of the BMD loss. For example, the most common therapies used to effectively treat the slow BMD loss observed in women with PMO (eg, oral bisphosphonates, calcium and vitamin D supplements) may not be optimal for prevention of accelerated BMD loss secondary to chemotherapy-induced menopause, the use of gonadotropin-releasing hormone (GnRH) analogues in premenopausal women, or AI therapy in postmenopausal women.
Monitoring and treatment recommendations to reduce fracture risk in women with early breast cancer
Bone health assessment in women undergoing adjuvant therapy for breast cancer should include BMD T-score measurement at baseline and at least every 1 to 2 years during treatment, together with assessment of established risk factors for fracture, as defined by an international expert panel . Women with moderate to severe osteopenia or additional fracture risk factors should receive bone-targeted treatment. Treatment should be continued for the duration of endocrine therapy. Currently there are no approved therapies specifically for preventing BMD loss in women receiving treatment for BC, although several recent clinical trials have sought to address this issue. The most robust data currently available in terms of the numbers of patients treated and duration of follow-up (for safety and efficacy) support the use of zoledronic acid (4 mg twice a year) to prevent CTIBL/AIBL in women receiving adjuvant endocrine therapy [42–44]. Smaller trials also support the activity of oral bisphosphonates and the new antiresorptive agent denosumab in this setting [39–41]. Although none of these trials specifically addressed the influence of clinical risk factors on fracture risk in this patient population, it is logical to infer that bone-directed therapy will be essential in women receiving AIs who also have multiple fracture risk factors. In addition, the delay in disease recurrence observed in the trials of zoledronic acid supports the potential for anticancer benefits from a therapy designed to preserve bone integrity [44–46]. Ongoing trials are evaluating whether other bisphosphonates and denosumab might also provide similar benefits, and the results are eagerly awaited.
Austrian Breast And Colorectal Cancer Study Group Trial-12
aromatase inhibitor-associated bone loss
American Society of Clinical Oncology
bone mineral density
cancer treatment-induced bone loss
deep vein thrombosis
Hormone Ablation Therapy in Breast Cancer
National Osteoporosis Foundation
National Osteoporosis Risk Assessment
Study of Anastrozole with the Bisphosphonate RisedronatE
Women's Health Initiative Observational Study
World Health Organization
Zometa/Femara Adjuvant Synergy Trials.
Peter Aitken, PhD, assisted with the preparation of this manuscript. Funding for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. I thank Shalini Murthy, PhD, ProEd Communications, Inc.®, for medical editorial assistance with this manuscript.
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