Aromatase Inhibitor-induced Bone Loss Research Articles

Aromatase inhibitor-induced bone loss osteosarcopenia in older patients with breast cancer: effects of the RANK/RANKL system's inhibitor denosumab vs. bisphosphonates.

The raising number of older patients who are diagnosed with breast cancer represents a significant medical and societal challenge. Aromatase inhibitors (AI), which are commonly utilized to treat this condition in these patients have significant adverse events on bone and muscle health. Falling estrogen production leads to an increase in RANKL secretion by osteoblasts with accelerated bone remodeling due to osteoclast activity. Furthermore, estrogen deficiency reduces skeletal muscle strength and mass. The humanized monoclonal antibody, denosumab, neutralizes RANKL, thereby inhibiting osteoclast formation, function and survival and ultimately exerting powerful anti-resorptive effects.. In this study, we report on the efficacy of denosumab in mitigating aromatase inhibitor-induced bone loss (AIBL) and sarcopenia in older women with breast cancer. From January 2022 to January 2023, we enrolled 30 patients (female sex, ≥ 65years) diagnosed with non-metastatic breast cancer undergoing adjuvant endocrine therapy; patients received, as per clinical practice, primary bone prophylaxis with denosumab (60mg via subcutaneous injection every 6months) according to oncologic guidelines. This group was matched with 30 patients with non-metastatic breast cancer, who were treated with biphosphonates (BF) therapy (oral alendronate 70mg/week). For each patient bone mineral density (BMD) and bone quality in terms of trabecular bone score (TBS) in addition to body composition and Relative Skeletal Muscle Index (RSMI) was assessed by bone densitometry at baseline and after one year of treatment. Significant improvements in TBS at the lumbar spine, RSMI and whole-body composition (arms, legs, and trunk) were observed in the denosumab group compared with the BF group. These findings underscore the role of denosumab as an effective strategy in managing AIBL and osteosarcopenia in older women with breast cancer and undergoing adjuvant endocrine therapy, which is crucial for improving quality of life, preventing functional decline, and optimizing treatment outcomes.

Prevention of aromatase inhibitor-induced bone loss with anti-resorptive therapy in post-menopausal women with early-stage breast cancer.

This study aimed to describe changes in femoral and lumbar bone mineral density (BMD) after 24months of aromatase inhibitors (AIs) and antiresorptive treatment in postmenopausal women with estrogen receptor-positive breast cancer. Prospective, longitudinal study in a real-life setting with a 2-year follow-up. Patients underwent a complete baseline bone assessment including clinical assessment, biological evaluation, BMD measurement, and spine X-ray. Antiresorptive treatment was prescribed to patients with a T-score < - 2 or a T-score < - 1.5 SD with additional osteoporosis risk factors. A follow-up bone assessment was carried out after 24months. Among 328 patients referred to our center, 168 patients (67.7 ± 10.6years) were included in our study, and 144 were eligible for antiresorptive treatment. After 24months, patients receiving antiresorptive treatment experienced a significant increase of + 6.28% in femoral-BMD (F-BMD) and + 7.79% in lumbar-BMD (L-BMD). This increase was not significantly different between osteoporotic and osteopenic patients. Conversely, patients not receiving antiresorptive treatment presented significant F-BMD and L-BMD loss regardless of the baseline BMD. In the multivariate logistic model, the lack of antiresorptive treatment was the only predictive factor for major femoral bone loss with a 20.83 odds ratio (CI95%:4.2-100, p < 0.001). This real-life study confirmed that antiresorptive treatment significantly increases femoral and lumbar BMD regardless of the baseline BMD in postmenopausal patients receiving AIs for early breast cancer. Patients who did not receive antiresorptive treatment had a 20.8-fold increased risk of major bone loss. Nevertheless, the best threshold to adopt for starting antiresorptive agents remains undetermined.

Aromatase Inhibitor Induced Bone Loss: Do International Guidelines Accurately Stratify Fracture Risk and Selection of Anti-Osteoporosis Treatment?

Abstract Introduction: Aromatase inhibitors (AI) are used for adjunctive treatment of estrogen receptor-positive (ER+) breast cancer. Aromatase converts androgens to estrogens in the ovaries and peripheral tissues such as adipose, liver, muscle, and breast. In breast, estrogens increase cell proliferation in both normal and ER+ malignant tissue. AIs globally suppress estrogen production, and thereby can decrease tumor progression. However, in bone, estrogens suppress osteoclast activity and decrease bone resorption so AI use results in increased bone resorption and decreased bone mineral density (BMD). Several guidelines exist to direct management of AI-associated bone loss, but it is unclear whether adherence to these guidelines translates to decreased fracture risk. The International Osteoporosis Foundation (IOF) et al 2017 guidelines for the prevention of osteoporotic fractures in patients treated with AI recommended BMD measurement at the onset of AI use and use of anti-osteoporosis therapy (anti-OP) in those who met T-score and clinical risk factor (CRF) criteria. Hypothesis: We explored application of these guidelines and whether they were able to stratify patients according to risk, initiation of treatment, and fracture outcomes. Methods: 1517 charts were extracted from the electronic medical record (EMR) of a tertiary academic medical center based on history of breast cancer and use of AIs between 2008 and 2017. Charts were retrospectively analyzed to determine baseline BMD, osteoporosis risk factors, duration of AI use, duration of anti-OP therapy, and fractures. The IOF criteria were applied to each patient to determine applicability of anti-OP therapy. Fracture rates were compared using chi square test or Fisher’s exact test. Results: 1517 patients were included in the analysis. Regardless of whether criteria were met for treatment based on baseline BMD and CRF, the fracture rate was significantly higher in the treated versus the untreated group, 13.78% (CI: 9.56–18.99) versus 2.24% (p &amp;lt; 0.0001, CI: 1.51–3.21). Similarly, among those that met criteria, the fracture rate was significantly higher in the treated versus the untreated group, 10.24% (CI: 5.56–16.87) versus 2.61% (p = 0.0005, CI: 1.20–4.89). There was no significant difference in fractures between those who did versus did not meet treatment criteria, 4.66% (CI: 2.94–6.97) versus 3.64% (p = 0.34, CI 2.59–4.96). Conclusions: This retrospective EMR analysis of 1517 breast cancer patients on AIs between 2008 and 2017 observed a higher fracture incidence in patients who received anti-OP treatment compared to those who did not, regardless of meeting criteria for treatment per the IOF guidelines. It is possible that patients who initiated anti-OP therapy had additional CRFs not captured in the EMR and not factored into our analyses.

Challenges in Preventing Bone Loss Induced by Aromatase Inhibitors.

Aromatase inhibitors have become a mainstay in the adjuvant treatment regimen in postmenopausal women with hormone receptor-positive breast cancer. While many of these patients have an excellent long-term prognosis, adverse effects on bone represent an emerging complication of aromatase inhibitor treatment, resulting in substantial bone loss and fragility fractures. Treatment approaches to prevent aromatase inhibitor-induced bone loss typically consist of an antiresorptive approach with bisphosphonates or the RANKL antibody denosumab. However, different guidelines vary with respect to treatment thresholds, duration, and dosing. The choice of antiresorptive regime is further complicated by comorbidities and potential disease-modifying effects of individual agents. This review summarizes the evidence of how aromatase inhibitors affect bone health and provides an update of clinical approaches to preserve bone strength in affected women. (J Clin Endocrinol Metab XX: 0-0, 2020).

Assessment of Aromatase Inhibitor-Induced Bone Loss and Appropriateness of Supportive Therapy in Postmenopausal Breast Cancer Patients at a Tertiary Care Center

Objective: To assess aromatase inhibitor-induced bone loss (AIBL) and its management in postmenopausal women (PMW) with breast cancer (BC). Materials and Methods: A cohort of 350 PMW with BC receiving aromatase inhibitors (AIs) during a span of 4 years was evaluated retrospectively. Bone mineral density (BMD) of the patients at lumbar spine (LS) and dual femur was monitored at baseline and annually for 2 years. Baseline fracture risk was evaluated using WHO fracture risk assessment tool. Results: At baseline, only 35.4% of the patients received supportive therapy such as calcium and Vitamin D supplements ± bisphosphonates. Significant decrease of mean BMD occurred at LS, left femur, and right femur (LF and RF) at 1 year (P

Bone and calcium metabolism associated with malignancy. Clinical Characteristics and Treatment of Cancer Treatment Induced Bone Loss(CTIBL)in Breast Cancer.

Breast cancer is a typical hormone-dependent tumor and at the time of diagnosis more than 60% of breast cancers are positive for estrogen receptors and estrogen(E)is required for proliferation. Since breast cancer is a tumor easily to cause micrometastasis, adjuvant hormonal therapy(HT)for 5 to 10 years after surgery that suppresses the action of estrogen actively prevents recurrence is very popular. However, HT with aromatase inhibitor(AI)for postoperative postmenopausal breast cancer markedly reduces the E concentration in the body, leading to significant bone loss and fracture as known as aromatase inhibitor-induced bone loss(AIBL), a typical example of CTIBL. Under these circumstances, the usefulness of bone modifying agents as a supportive therapy to increase bone density and decrease fracture rate without interrupting the treatment of breast cancer became clear, mainly in Europe and the United States. And recently, our study revealed even in Japanese breast cancer patients denosumab injection every 6 months showed significant increase in bone density. The number of women suffering from breast cancer in Japan reaches approximately 90,000 per year, a considerable number is estimated as a preliminary group of CTIBL, so early appropriate measures are desired.

Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.

Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.

Management of aromatase inhibitor-induced bone loss in breast cancer patients

Management of aromatase inhibitor-induced bone loss in breast cancer patients

Abstract P1-12-11: Prospective study of aromatase inhibitor-induced bone loss and lipid levels in early hormone sensitive breast cancer treated with AI during 8 years

Abstract Introduction: AI’s are the preferred adjuvant hormonal treatment for postmenopausal(PM) estrogen receptor positive (ER+) disease because of the improved efficacy over tamoxifen in terms of disease free survival and reduction in distant recurrence. AI’s have been associated with increased bone loss by blocking peripheral tissue estrogen synthesis, arthralgia and a negative effect on lipid metabolism. In this prospective study we wanted to assess the amount of bone loss and the changes in lipid levels in early breast cancer(EBC) patients (pts) treated with 3yrs of extended letrozole as part of the SOLE study after 5 yrs of adjuvant AI. Objectives: the primary objective of the study is to calculate the mean percentage change in bone mineral density(BMD)(g/cm2) after 8 yrs of letrozole and to compare between the continuous(C) and intermittent(I) intake of letrozole. The secondary objectives are to correlate the mean change in BMD with the initial value, BMI and to describe the evolution of the lipid levels in both groups. Patients and methods: BMD was measured at the lumbar spine (L2-4) and hip by dual energy X-ray absorptiometry (DEXA) in PM pts. with ER+ EBC. We also measured the fasting lipid levels baseline and after 8 yrs of an AI. Differences between the two groups were assessed by the independent samples T-test and the correlation by the linear regression analysis. Results: Fifty four pts were included in the study with a mean age of 62.5 yrs(+/-8.6 yrs). Seventeen pts are too early to be evaluable, 8 pts stopped letrozole due to adverse events and 2 pts had no baseline DEXA values. Two pts received tamoxifen 2 to 5 yrs before inclusion in the SOLE study. The remaining 25 pts showed a mean change in BMD for the lumbar spine of -1.1 (10.6SD) and for the hip -4.4 (7.04SD). Currently 13 pts in the C arm demonstrated a mean decrease in BMD for the (LS) of -2.7(10.2SD), and for the hip of -2.7(5.5SD). Twelve pts included in the I arm experienced a mean increase in BMD for the LS of 0.65(SD11.2) and a mean decrease in BMD for the hip of -4.9(9.1SD). The difference between the two treatment groups was not significant for the LS measurements after 8yrs (p=0.4) nor for the hip (p=0.23) neither was it at baseline (p=0.9; 0.1). Only three pts had fractures due to trauma. The overall fracture rate was only 0.05%.There was no correlation with the BMI, but there was a significant correlation with baseline BMD.(p=0.002)The mean fasting cholesterol levels at 8yrs in the C arm was 214mg/dl(41.3SD) and in the I arm was 218mg/dl(35.6SD)and was not significantly different(p=0.8), nor was it at baseline(p=0.5). Conclusion: This first prospective long term BMD and lipid follow-up study in PM EBC pts taking adjuvant letrozole beyond 5 yrs shows a decline in BMD. Until now no significant differences were observed between continuous and intermittent letrozole. An updated and detailed follow-up on more patients will be presented. Citation Format: Christel Fontaine, Lore Decoster, Denis Schallier, Leen Vanacker, Jacques De Grève, Marian Vanhoeij, Guy Verfaillie, Jan Lamote. Prospective study of aromatase inhibitor-induced bone loss and lipid levels in early hormone sensitive breast cancer treated with AI during 8 years [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-11.

The efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss for postmenopausal women with early breast cancer: a systematic review and meta-analysis.

Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL) in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329–21.959, P value = 0.018) and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249–7.143, P value = 0.0002). Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR's than patients with delayed ZOL.

Guidelines for diagnostics and treatment of aromatase inhibitor-induced bone loss in women with breast cancer: A consensus of Lithuanian medical oncologists, radiation oncologists, endocrinologists, and family medicine physicians

The aim of this article is to inform about cancer treatment-induced bone loss, to identify patients at risk and those that can benefit from bone targeted treatment as well as highlight the importance of the multidisciplinary approach in the bone health in cancer care. Patients with breast cancer treated or intended to be treated with aromatase inhibitors belong to a high-risk group because their fracture risk increases up to 30% due to a significant decrease in bone mineral density within 6–12 months after the start of hormonal treatment. To evaluate bone status and predict risk for fractures, lateral thoracic and lumbar spine X-ray imaging, bone mineral density measurement by dual energy X-ray absorptiometry at the lumbar spine L1–L4 vertebrae and/or hip and fracture risk factors assessment are mandatory tests prior to hormonal treatment. Morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle interventions, and therapy. Algorithm for the management of bone health in breast cancer patients was established in Lithuania to screen patients with increased risk for bone loss and to provide adequate specific osteoporosis treatment.

Breast cancer and osteoporosis

Over the past few years, a number of studies have examined the relationship between breast cancer and osteoporosis, the effect of breast cancer treatment on bone health, and the effect of osteoporosis therapies on aromatase inhibitor-induced bone loss and breast cancer recurrence. New guidelines have been released on the prevention of osteoporotic fractures in women with breast cancer who are on aromatase inhibitors for adjuvant therapy. Despite common factors linking high bone mineral density and increased risk of breast cancer, women with breast cancer are not protected from osteoporosis or osteoporotic fractures. Recent data suggest that aromatase inhibitors have a detrimental effect on bone mineral density and can increase the risk of fractures. Bisphosphonate therapy not only preserves aromatase inhibitor-induced bone loss, but may also improve disease-free survival and decrease risk of death in select women with breast cancer (i.e., postmenopausal women). Osteoporosis and breast cancer are common in women, especially in postmenopausal women. Current guidelines suggest that we need to pay special attention to those on aromatase inhibitors to prevent adverse bone outcomes.

Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial

Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures.In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1mg daily), calcium and vitamin D. ResultsAll osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm.At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate.There was a significant drop in lumbar spine (−5.4%) and hip (−4.5%) mean BMD, in the normal BMD group, none of whom received alendronate.Fracture data will be presented. ConclusionIn postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

P2-17-08: rospective Study of Aromatase Inhibitor Induced Bone Loss and Lipid Levels in Early Postmenopausal (PM) Hormone Receptor Positive (HR+) Breast Cancer (BC) Patients Treated with Adjuvant Letrozole Extended beyond 5 Years (yrs).

Abstract Introduction/Aim: Adjuvant treatment with aromatase inhibitors (AI) is associated with accelerated bone loss and increase in lipid levels. The effectiveness and tolerance of extended treatment with AI beyond 5 years is currently under investigation. In the SOLE study, five years of continuous (C) extended letrozole is compared to interrupted therapy (9 months on, 3 months off letrozole) after 5 yrs of tamoxifen, AI or sequential hormonal therapy. We have evaluated the bone mineral density and lipid levels during the extended use of letrozole beyond 5 yrs in a cohort of patients included in the SOLE study. Patients and methods: Postmenopauzal women with HR+ BC, receiving extended continuous (C) or intermittent (I) letrozole for 5 yrs after 5 yrs of tamoxifen, 5 yrs of an AI, or switch therapy within the first 5 years, were included. Bone mineral density was measured at the lumbar spine (L2-4) and total hip BMD (g/cm2), by dual energy X-ray absorptiometry (DXA). The mean percentage change in BMD at 12, 36 and 60 months (mths) was compared between the C and I treatment with letrozole and with baseline values. Differences between the treatment groups were assessed by the independent samples T test. We also compared the evolution ofthe serum lipid levels in both arms. Results: Thirty two patients (pts) were included with a mean age of 62 yrs (+/− 8.7 yrs). Thirty pts were valuable because of missing baseline DXA values in 2. In their first 5 years of adjuvant letrozole, prior to inclusion in the current study, twenty three pts had a mean percentage decrease of −0,76 (13,25 SD) and 7 pts who had received preventive zoledronate in the ZOFAST study, had a mean percentage increase in BMD of 4,4 (6,08 SD). Currently 12 pts receiving the continuous letrozole are evaluable after a first one year extension of adjuvant letrozole. They had a mean percentage increase in BMD for the lumbar spine of 1.8 (3.3 SD), and a mean percentage increase in BMD for the hip of 0.85 (SD 1.93). Eight pts included in the intermittent arm are evaluable. They experience a mean percentage decrease in BMD for the lumbar spine of −0.32(2.7 SD) and a mean decrease in BMD for the hip of −2.9(SD 3.6) The difference between the two treatment groups was not significant for the lumbar spine measurements (p=0.14), but it was significant for the hip (p=0.02). The mean fasting cholesterol levels at 12 months in the C arm (12pts) was 228mg/dl (24.4 SD) and in the I arm (11pts) was 225,5mg/dl(32,3 SD) (p=0.37). Conclusion: This is the first prospective BMD and lipid follow-up study during adjuvant letrozole extended beyond 5 yrs in PM early breast cancer pts. After the first year of extended intake of continuous or intermittent letrozole a possible difference in bone mineral density between the two arms is emerging, but the two groups are too small to make final conclusions. An updated longer follow-up on more patients will be presented. After one year no differential effect on cholesterol levels has been observed. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-08.

Cost-effectiveness of zoledronic acid (ZOL) for the treatment of bone loss in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the United States (US).

e11007 Background: Treatment guidelines recommend the use of bisphosphonates in postmenopausal women with early-stage breast cancer receiving prolonged aromatase inhibitor therapy and who are at high risk of fractures (e.g., in patients whose bone loss has become clinically significant, e.g., with bone mineral density BMD T score < 2 SD below normal, or who have experienced a fragility fracture). This retrospective modeling analysis assessed the cost-effectiveness of ZOL therapy versus no therapy for the treatment of aromatase inhibitor induced bone loss in US postmenopausal women with breast cancer. Methods: A model was developed to project the lifetime fractures incidence as a function of BMD. In the model, patients were assumed to receive aromatase inhibitors (i.e., letrozole [Femara] 2.5 mg daily), for 5 years with a starting T score of -2 or more. In one arm, patients initiated ZOL (4 mg IV infusion q 6 months) when their BMD T-score decreased to more than 2 SD below normal or had nontraumatic fracture. Data regarding the efficacy of this treatment arm came from the results of the US- based Z-FAST trial. In the comparison group, patients were assumed to receive no ZOL therapy. The progression of bone loss and risk of fracture in the no treatment group were obtained from the published epidemiologic literature. The model simulated the impact of fractures on costs, quality of life and mortality. Results: Compared to the no treatment arm, patients on the ZOL arm experienced a gain of 0.032 quality-adjusted life-years (QALYs), at the incremental costs of $47,995 per QALY. In a sensitivity analysis in which a Medicare payer perspective was adopted, whereby only 80% of costs are included, the costs/QALY improved to $38,396. Conclusions: The use of ZOL for the treatment of aromatase inhibitor induced bone loss in postmenopausal women with breast cancer whose bone loss has become clinically significant or who have experienced a fragility fracture appears cost-effective in the US. These results might be conservative as they exclude the potential benefits of ZOL on disease progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis

Prevention of Aromatase Inhibitor–Induced Bone Loss Using Risedronate: The SABRE Trial

PURPOSE To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. PATIENTS AND METHODS Postmenopausal women with hormone receptor-positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v -1.8%; treatment ratio, 1.04; P < .0001; and 1.8% v -1.1%; treatment ratio, 1.03; P < .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = .0109) and a numerical decrease in total hip BMD (-0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. CONCLUSION In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.

Targeting the tumour microenvironment: denosumab, a new RANKL inhibitor

Bone is the most common site for metastasis and is of particular clinical importance in breast cancer, which is common and associated with a relatively long clinical course. Metastatic bone disease results from the interactions between cancer cells in the bone marrow microenvironment and normal bone cells rather than direct destruction by cancer cells. These growth factor and cytokine-mediated interactions typically lead to stimulation of both osteoclast and osteoblast function with uncoupling and imbalance in bone remodelling. This provides the rationale for bone-targeted therapies to reduce the risk of skeletal complications such as fracture, and to relieve bone pain. Additionally, bone-derived growth factors released from bone promote a fertile environment for the survival and proliferation of cancer cells, creating a vicious cycle of bone destruction. Receptor activator of NF-κB ligand (RANKL) is a key mediator in this process. Within the bone microenvironment, factors secreted by tumour cells stimulate stromal cells and osteoblasts to secrete RANKL, which binds to its cognate receptor RANK on the surface of precursor and mature osteoclasts. RANKL is a critical mediator of osteoclast differentiation, function, and survival. Denosumab is a fully humanised monoclonal antibody that inhibits RANKL. A dose of 120 mg, 4-weekly, administered by subcutaneous injection has been defined in a large dose-finding randomised phase II study for the treatment of advanced malignancy [1]. To prevent treatment-induced bone loss, an osteoporosis dose and schedule of 60 mg every 6 months has been evaluated, and was shown to prevent aromatase inhibitor-induced bone loss [2]. The large phase III trials in metastatic bone disease comparing denosumab with zoledronic acid have completed accrual and will report in the next year. Preclinical data suggest that denosumab is a more complete inhibitor of osteoclast function than the bisphosphonates (BPs). Additionally, a randomised phase II study in patients with increased bone resorption despite ongoing BPs has compared changing to denosumab, an antibody to RANK ligand, with continuation of the BP. This showed rapid and sustained biochemical response in >80% of patients with denosumab compared with <30% for those on standard BP treatment. Additionally, the number of skeletal events appeared to be less in the denosumab-treated patients [3]. The Austrian Breast Cancer Study Group are conducting a large randomised trial in postmenopausal women receiving endocrine treatment with the 60 mg every 6 months schedule. This is primarily to evaluate effects on bone mineral density and fractures, but with disease-free survival as a secondary endpoint. Other metastasis prevention trials are planned.

Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer

Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss. Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.