Management of Cancer-Treatment–Induced Bone Loss in Postmenopausal Women Undergoing Adjuvant Breast Cancer Therapy: A Z-FAST Update

doi:10.1053/j.seminoncol.2006.03.022

Seminars in Oncology

Volume 33, Supplement 7, April 2006, Pages 13-17

https://doi.org/10.1053/j.seminoncol.2006.03.022 Get rights and content

The prevention of cancer-treatment–induced bone loss (CTIBL) in long-term adjuvant breast cancer therapy is a high priority. Postmenopausal women with cancer, already at increased risk of bone loss because of age-related estrogen deficiency, face accelerated bone loss with the use of estrogen-depleting therapies such as third-generation aromatase inhibitors (AIs). Although effective in reducing cancer recurrence rates in the adjuvant setting, AIs are associated with bone loss and an increased risk of fractures. Bisphosphonates, which act by inhibiting osteoclastic bone resorption, have been shown to increase bone mineral density (BMD) and reduce fracture risk in postmenopausal women with established osteoporosis. Furthermore, the potent bisphosphonate zoledronic acid has been shown to be efficacious in reducing bone loss in premenopausal women receiving combination adjuvant hormone therapy (goserelin, a gonadotropin-releasing hormone agonist, plus either an AI or tamoxifen). The use of zoledronic acid to prevent CTIBL in postmenopausal women receiving adjuvant AI therapy with letrozole is currently being investigated in the Zometa/Femara Adjuvant Synergy Trial (Z-FAST). Postmenopausal women with stage I-IIIa estrogen-receptor–positive and/or progesterone-receptor–positive breast cancer starting letrozole are randomized to receive either upfront zoledronic acid or delayed zoledronic acid. At 6 months, assessable women in the upfront group showed a mean increase of 1.55% in lumbar spine (L1 – L4) BMD, compared with a mean decrease of 1.78% in women in the delayed group, resulting in a difference of 3.33% between groups; moreover, women in the former group showed a mean increase of 1.02% in total hip BMD, compared with a mean decrease of 1.40% in those in the latter group, resulting in a significant difference of 2.42% between groups (P <.001). Thus, the Z-FAST BMD results show that upfront zoledronic acid prevents CTIBL in postmenopausal women receiving adjuvant letrozole therapy for early breast cancer. Combining the anticancer efficacy of letrozole with the bone-protective effect of zoledronic acid may be a successful treatment in this setting.

Section snippets

Aromatase Inhibitors as Adjuvant Therapy

Four phase III randomized trials compared the safety and efficacy of the third-generation AIs with tamoxifen or placebo as adjuvant or extended adjuvant therapy in postmenopausal women with breast cancer.

The randomized, double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial evaluated the effectiveness of anastrozole alone, tamoxifen alone, or anastrozole plus tamoxifen as adjuvant therapy for localized breast cancer in postmenopausal women.8, 12, 13, 14 The combination treatment

Strategies to Counteract Bone Loss During Adjuvant Treatment With AIs

Bisphosphonates are an important class of drugs that act by inhibiting osteoclastic bone resorption.¹⁰ Oral bisphosphonates are widely used in the treatment of postmenopausal osteoporosis. Nitrogen-containing oral bisphosphonates (eg, alendronate, risedronate) have been shown to increase BMD and decrease fracture occurrence in women with established postmenopausal osteoporosis.²⁰ Long-term patient compliance, however, may be limited by gastrointestinal intolerance that in turn limits optimal

Z-FAST Results

Z-FAST is a randomized, open-label, multicenter trial designed to compare the safety and efficacy of upfront versus delayed zoledronic acid treatment in preventing CTIBL in postmenopausal women with hormone-receptor–positive breast cancer who are also receiving adjuvant therapy with letrozole. Accrual was completed in December 2003, with 602 patients enrolled at 93 sites in the United States and Canada.²² The companion ZO-FAST study has completed accrual of more than 1,000 patients at 112

Conclusion

The prevention of CTIBL in long-term adjuvant breast cancer therapy is a high priority. Changes in BMD during such therapy in postmenopausal women can be easily monitored and addressed with the coadministration of zoledronic acid. The Z-FAST results show that combining the anticancer efficacy of letrozole with the bone-protective effect of zoledronic acid is an effective way to prevent CTIBL.

Upfront zoledronic acid was shown to prevent CTIBL in postmenopausal women receiving adjuvant letrozole

References (24)

M. Gnant et al.
Zoledronic acid inhibits cancer treatment-induced bone loss in premenopausal patients with breast cancer who are receiving adjuvant endocrine treatment
Breast
(2005)
H.A. Harvey
Optimizing bisphosphonate therapy in patients with breast cancer on endocrine therapy
Semin Oncol
(2004)
F. Boccardo
Switching trial of adjuvant tamoxifen with an aromatase inhibitor in postmenopausal patients with breast cancer
Clin Breast Cancer
(2004)
R. Jakesz et al.
Switching of postmenopausal women with endocrine responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifencombined results of ABCSG trial 8 and ARNO 95 trial
Lancet
(2005)
N. Davidson et al.
Zoledronic acid in the prevention of cancer treatment-induced bone loss in postmenopausal women receiving letrozole as adjuvant therapy for early breast cancer
Breast
(2005)
M.S. Aapro
Long-term implications of bone loss in breast cancer
Breast
(2004)
J. Pfeilschifter et al.
Osteoporosis due to cancer treatmentPathogenesis and management
J Clin Oncol
(2000)
J.R. Mackey et al.
Skeletal health in postmenopausal survivors of early breast cancer
Int J Cancer
(2005)
E.P. Winer et al.
American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancerStatus report 2004
J Clin Oncol
(2005)
R.C. Coombes et al.
A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer
N Engl J Med
(2004)

P.E. Goss et al.

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer

N Engl J Med

(2003)

M. Baum et al.

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancerResults of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses

Cancer

(2003)

Cited by (54)

Updated guidance on the management of cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer
2021, Journal of Bone Oncology
Adjuvant endocrine therapy induces bone loss and increases fracture risk in women with hormone-receptor positive, early-stage breast cancer (EBC). We aimed to update a previous position statement on the management of aromatase inhibitors (AIs) induced bone loss and now included premenopausal women.
We conducted a systematic literature search of the medical databases from January 2017 to May 2020 and assessed 144 new studies.
Extended use of AIs beyond 5 years leads to persistent bone loss in breast cancer extended adjuvant trials and meta-analyses. In addition to bone mineral density (BMD), vertebral fracture assessment (VFA) and trabecular bone score (TBS) were shown to independently predict fracture risk in real life prospective studies. FRAX® tool does not seem to be reliable for assessing fracture risk in CTIBL. In premenopausal women, there is strong evidence that intravenous zoledronate prevents bone loss but weak conflicting evidence on reducing disease recurrence from independent randomised controlled trials (RCTs). In postmenopausal women, the strongest evidence for fracture prevention is for denosumab based on a well-powered RCT while there is strong evidence for bisphosphonates (BPs) to prevent and reduce CTIBL but no convincing data on fractures. Adjuvant denosumab has failed to show anticancer benefits in a large, well-designed RCT.
Extended use of AIs and persistent bone loss from recent data reinforce the need to evaluate fracture risk in EBC women initiated on AIs. Fracture risk should be assessed with clinical risk factors and BMD along with VFA, but FRAX is not adapted to CTIBL. Anti-resorptive therapy should be considered in those with a BMD T-score < −2.0 SD or with ≥ 2 clinical risk factors including a BMD T-score < −1.0 SD. In premenopausal women, intravenous zoledronate is the only drug reported to prevent bone loss and may have additional anticancer benefits. In postmenopausal women, either denosumab or BPs can be prescribed for fracture prevention with pertinent attention to the rebound phenomenon after stopping denosumab. Adjuvant BPs, in contrast to denosumab, have shown high level evidence for reducing breast cancer recurrence in high-risk post-MP women which should be taken into account when choosing between these two.
Link between estrogen deficiency osteoporosis and susceptibility to bone metastases: A way towards precision medicine in cancer patients
2018, Breast
Citation Excerpt :
Thirdly, another key field includes the side-effects on reproductive hormones of several treatments used for the management of cancer patients [6]. Particularly, hormonal-ablative treatments in women with hormone receptor-positive cancers lead to a rapid increase in bone resorption [7,8]. Reproductive hormones play a key role in normal bone remodeling maintenance, and estrogen deprivation in women with breast cancer will lead to accelerated bone loss and increased risk of osteoporosis (OP), with related fractures that have a significant negative impact on the life of cancer patients [9].
Different fields of cancer management consider bone health to be of increasing clinical importance for patients: 1) presence of bone metastases in many solid tumors, 2) use of bone-targeted treatments in the reduction of bone metastasis, 3) effects of cancer treatment on reproductive hormones, critical for normal bone remodeling maintenance. Additionally, bone microenvironment is further complicated by the decline of ovarian sex steroid production and by the related increase in inflammatory factors linked to menopause, which result in accelerated bone loss and increased risk of osteoporosis (OP). Similarly, cancers and metastasis to bone showed a close relationship with sex hormones (particularly estrogen). Thus, these findings raise a question: Could pre-existing estrogen deficiency OP promote and/or influence cancer cell homing and tumor growth in bone? Although some preclinical and clinical evidence exists, it is mandatory to understand this aspect that would be relevant in the clinical theatre, where physicians need to understand the treatments available to reduce the risk of skeletal disease in cancer patients. This descriptive systematic review summarizes preclinical and clinical studies dealing with bimodal interactions between pre-existing estrogen deficiency OP and bone metastasis development and provides evidence supporting differences in tumor growth and colonization between healthy and OP status. Few studies evaluated the impact of estrogen deficiency OP on the susceptibility to bone metastases. Therefore, implementing biological knowledge, could help researchers and clinicians to have a better comprehension of the importance of pre- and post-menopausal bone microenvironment and its clinical implications for precision medicine in cancer patients.
Antiresorptive therapies in oncology and their effects on cancer progression
2012, Cancer Treatment Reviews
Bone health is an emerging concern in the early breast cancer setting. Current adjuvant therapies, especially hormonal therapies in premenopausal patients (e.g. goserelin) and aromatase inhibitors in postmenopausal patients, have been associated with substantial decreases in bone mineral density that may place patients at risk for fractures. Bisphosphonates—and the recently approved anti-RANKL antibody, denosumab—have both demonstrated activity for the treatment of postmenopausal osteoporosis and cancer treatment-induced bone loss (CTIBL) in breast cancer patients, although neither has received widespread approval specifically for CTIBL. However, some bisphosphonates, especially the nitrogen-containing bisphosphonate zoledronic acid, have also demonstrated clinically meaningful anticancer effects in patients receiving adjuvant hormonal therapy for breast cancer and in other oncology settings. The effects of denosumab on cancer disease outcomes in the adjuvant setting remain to be established. This discrepancy has created a dilemma in terms of how to evaluate the complete benefit:risk profile of bone-health management options in the adjuvant breast cancer setting. This review summarises the current data on the course of cancer in clinical trials of the antiresorptive agents and provides important insight into the relative anticancer potential of the various therapies.
Dosing of zoledronic acid throughout the treatment continuum in breast cancer
2011, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Moreover, because most nitrogen-containing BPs showed promising antitumor and antimetastatic activities in vitro [73], an evolving goal of recent trials was to evaluate the activity of BPs for preventing bone metastasis and improving overall clinical outcomes including disease-free and recurrence-free survival (DFS and RFS, respectively). Recent data from phase III trials support twice-yearly ZOL dosing to preserve BMD during adjuvant endocrine therapy in the early breast cancer setting (stage I to IIIa) [53–56]. In the 3 companion studies Z-FAST (N = 602), ZO-FAST (N = 1065), and E-ZO-FAST (N = 523), upfront ZOL (4 mg q6mo) prevented AIBL and improved BMD versus baseline in postmenopausal women receiving adjuvant letrozole therapy [75–78].
Several bisphosphonates including zoledronic acid (ZOL) are approved for treating bone metastases from breast cancer (BC). Recent trials demonstrated that ZOL prevents bone loss and reduces disease recurrence in early BC. This review uses pharmacodynamic, efficacy, and safety data from phase III trials of ZOL in early through metastatic BC to evaluate the dosing regimens used in each setting. The dosing frequencies of ZOL in early stage versus metastatic BC (4 mg 2–4 times per year versus monthly) are based on the respective levels of bone resorption and tumor burden. Data from ongoing clinical trials suggest that monthly dosing facilitates potential synergy between ZOL and chemotherapy in intermediate-risk BC and during neoadjuvant therapy. Overall, available data indicate that treatment with ZOL at appropriate intervals determined by disease characteristics helps attain key therapeutic goals in BC—maintaining skeletal integrity, reducing disease recurrence, and improving clinical outcomes.
Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial
2011, Annals of Oncology
Citation Excerpt :
The latest results from the main ATAC trial and bone sub-protocol show that, on completion of anastrozole treatment, fragility fracture rates decrease back to levels similar to those observed with tamoxifen, and fractures occurring after treatment completion are not associated with patients becoming osteoporotic after AI treatment. Overall, the prevention of CTIBL in long-term adjuvant AI breast cancer therapy remains a high priority [25]. What these study results demonstrate is that, in contrast to the beneficial effects of anastrozole on breast cancer recurrence which extend substantially beyond the cessation of treatment [14], anastrozole-associated BMD loss begins to resolve immediately after treatment cessation and any bone loss associated with anastrozole can be monitored and managed as needed [25–29].
This ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial sub-study examined the effects of anastrozole and tamoxifen on bone mineral density (BMD) following 5 years of treatment.
Lumbar spine and total hip BMD were assessed at years 6 and 7 in a total of 71 eligible patients. In total, 50 patients had evaluable data.
Following anastrozole treatment, the lumbar spine median BMD increased by 2.35% (P = 0.04) and 4.02% (P = 0.0004) at years 6 and 7, while total hip median BMD increased by 0.71% (P = 0.3) and 0.5% (P = 0.8). After tamoxifen treatment, lumbar spine median BMD decreased by 0.79% (P = 0.2) and 0.30% (P = 0.9) at years 6 and 7, while total hip median BMD decreased by 2.09% (P = 0.0003) and 2.52% (P = 0.0002). Patients with a normal BMD or who were osteopenic at 5 years did not become osteoporotic.
Anastrozole treatment-related bone loss did not continue into the off-treatment follow-up period. The recovery in lumbar spine BMD and absence of further loss at the hip is consistent with the reduction in the annual rate of fracture observed after treatment cessation in the main ATAC trial.
Aromatase Inhibitors and Their Side Effects: What Hand Surgeons Should Know
2010, Journal of Hand Surgery

View all citing articles on Scopus

¹: Dr Brufsky has received research grant support and honoraria from Novartis.

View full text

Management of Cancer-Treatment–Induced Bone Loss in Postmenopausal Women Undergoing Adjuvant Breast Cancer Therapy: A Z-FAST Update

Section snippets

Aromatase Inhibitors as Adjuvant Therapy

Strategies to Counteract Bone Loss During Adjuvant Treatment With AIs

Z-FAST Results

Conclusion

Breast

Semin Oncol

Clin Breast Cancer

Lancet

Breast

Long-term implications of bone loss in breast cancer

Breast

Osteoporosis due to cancer treatmentPathogenesis and management

J Clin Oncol

Skeletal health in postmenopausal survivors of early breast cancer

Int J Cancer

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancerStatus report 2004

J Clin Oncol

A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer

N Engl J Med

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer

N Engl J Med

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancerResults of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses

Cancer