Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC

Abstract

Postmenopausal women with breast cancer (BC) are at increased risk for bone loss. Bisphosphonates improve bone mineral density (BMD) in normal postmenopausal women. The purpose of this study was to determine if immediate treatment with zoledronic acid preserves BMD in postmenopausal women with BC starting letrozole after tamoxifen. Postmenopausal women with BC completing tamoxifen were treated with daily letrozole 2.5 mg/vitamin D 400 I.U., calcium 500 mg twice daily and were randomized to upfront or delayed zoledronic acid 4 mg every 6 months. Patients in the delayed arm were only given zoledronic acid if they developed a post-baseline BMD T score <−2.0 or had a fracture. The primary endpoint was the mean percent change in lumbar spine (LS) BMD at 1 year. About 558 women enrolled; 395 provided 1 year BMD data. The upfront arm experienced a mean change of +3.66% in LS BMD versus -1.66% for the delayed group (P < 0.001). Changes at the femoral neck/total hip were also greater for the upfront versus delayed arms (P < 0.001; P < 0.001) with differences persisting at 2 years. Patients in the delayed arm were more likely to experience a clinically meaningful 5% loss of BMD at all sites versus the upfront zoledronate group. Patients in the upfront arm were slightly more likely to report limb edema, fatigue, fever, nausea and jaw osteonecrosis(1%). Upfront zoledronic acid prevents bone loss in postmenopausal women with BC starting letrozole after tamoxifen.

Final 5‐year results of Z‐FAST trial

“…Original Article received 2 years of letrozole after 6 years of tamoxifen, Hines and colleagues observed significant losses in BMD in the delayed group (LS, À2.3%; total hip, À3.3%) compared with the upfront group (LS, 4.9%; total hip, À1.2%), findings similar to those observed in the current study. 15 Regardless of baseline T score, chemotherapy status, or the presence of risk factors, we observed significant and progressive increases in LS and total hip BMD throughout the study with the initiation of zoledronic acid at study randomization; in contrast, significant decreases occurred when zoledronic acid initiation was delayed until bone loss was apparent. Over time, the rate of BMD decline in the delayed group slowed (see Fig.…”

“…15,17 The final results of the bone substudy of the Austrian Breast and Colorectal Cancer Study Group-12 trial (N ¼ 1803), which evaluated zoledronic acid (4 mg IV every 6 months) in 404 premenopausal women with hormone-responsive breast cancer receiving goserelin and either anastrozole or tamoxifen, demonstrate significant increases in BMD (LS, þ4% [P ¼ .02]; trochanter, þ3.9% [P ¼ .07]) compared with baseline values at 5 years, even 2 years after therapy cessation. 17 Conversely, women receiving endocrine therapy alone (no zoledronic acid) experienced significant decreases in BMD (LS, À6.3% [P ¼ .001]; trochanter, À4.1% [P ¼ .06]) at 5 years.…”

“…[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The prevention and treatment of bone loss with upfront (initiated simultaneously with letrozole) versus delayed (initiated with a decrease in T score to <À2 or occurrence of clinical nontraumatic fracture) zoledronic acid in early breast cancer patients receiving letrozole was evaluated in 3 similarly designed, geographically diverse studies (Z-FAST; ZO-FAST; E-ZO-FAST) and in the similarly-designed N03CC study. 15 Interim (<36 months follow-up) results from the former 3 studies indicate that upfront rather than delayed-start zoledronic acid is significantly more effective in preventing bone loss. 2,3,13,14 This article reports the final, 5-year results of the Z-FAST study.…”

“…2,12 In addition, zoledronic acid has been shown to increase bone mineral density (BMD) in premenopausal and postmenopausal breast cancer patients at risk of cancer treatment-induced bone loss. 2,3,[13][14][15][16][17] Recently, preclinical and clinical data have also demonstrated anticancer effects of bisphosphonates in breast and other cancer types. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The prevention and treatment of bone loss with upfront (initiated simultaneously with letrozole) versus delayed (initiated with a decrease in T score to <À2 or occurrence of clinical nontraumatic fracture) zoledronic acid in early breast cancer patients receiving letrozole was evaluated in 3 similarly designed, geographically diverse studies (Z-FAST; ZO-FAST; E-ZO-FAST) and in the similarly-designed N03CC study.…”

Cost–Utility of Adjuvant Zoledronic Acid in Patients with Breast Cancer and Low Estrogen Levels

“…Many of the completed trials investigated adjuvant bisphosphonate therapy for its effect on bone health [7][8][9][10][11][12] . Those trials often compared early with delayed bisphosphonate therapy rather than adjuvant za with no bisphosphonate, or considered primary endpoints that were unrelated to breast cancer outcomes.…”