BTA
Several clinical trials have investigated the role of BP in the management of BC-associated CTIBL; the most important are summarised in Table
2. The earliest results came from small studies exploring the efficacy of oral clodronate. Postmenopausal women treated with adjuvant tamoxifen or toremifene were randomised to the clodronate or control group for 3 years, where clodronate was associated with a small BMD improvement at both LS (+ 1.0 vs. − 1.7%,
p = 0.01) and FN (+ 2.4 vs. − 0.4%,
p = 0.12), as compared to patients not receiving the BP [
96].
Table 2
Clinical trials investigating the efficacy of bisphosphonates in preventing AI-induced CTIBL
ARIBON | 131 | 24 | Anastrozole + ibandronate | Anastrozole + placebo | + 2.98 vs. − 3.22% | |
SABRE | 234 | 24 | Anastrozole + risedronate | Anastrozole + placebo | + 2.2 vs. − 1.8% | |
IBIS II bone sub-study | 1410 | 36 | Anastrozole + risedronate | Anastrozole + placebo | + 1.1 vs. − 2.6% | |
Z-FAST | 602 | 61 | Letrozole + upfront ZA | Letrozole + upfront ZA | + 6.18–6.22 vs. − 2.42% | |
ZO-FAST | 1065 | 60 | Letrozole + upfront ZA | Letrozole + delayed ZA | + 4.3 vs. − 5.4% | |
E-ZO-FAST | 527 | 12 | Letrozole + upfront ZA | Letrozole + delayed ZA | + 2.72 vs. − 2.71% | |
The ARIBON trial reported that 2-year treatment with ibandronate induced a significant BMD gain at both LS and hip (+ 2.98 and + 0.60%,
p < 0.01 for both) in osteopaenic postmenopausal women treated with adjuvant anastrozole [
97]. Patients who continued ibandronate treatment up to 5 years underwent a mean lumbar BMD increase of + 3.19%, while those stopping the BP showed a BMD reduction at both LS (− 3.21%) and hip (− 5%) at the 5-year follow-up [
98].
The efficacy of oral risedronate in postmenopausal women was investigated in both the SABRE trial and the IBIS II study. SABRE reported that those at moderate or high risk of fragility fractures significantly benefited from the addition of risedronate to adjuvant AI treatment [
99]. IBIS II investigated the effect of anastrozole or placebo for BC prevention in women who were at high risk of BC. Those with osteopaenia or osteoporosis at baseline were included in a sub-study to assess bone protection with risedronate. After 3 years, the addition of risedronate to anastrozole was associated with a 1.1% (95% CI 0.2–2.1) increase in LS BMD compared to a 2.6% (95% CI − 4.0 to − 1.3) decrease with placebo (
p < 0.0001) in osteopaenic women; among osteoporotic patients, those receiving placebo and risedronate experienced a greater gain in BMD at LS (3.9 vs. 1.2%,
p = 0.006) and hip (1.5 vs. 0.3%,
p = 0.12) than those treated with anastrozole with risedronate, but the BP still counterbalanced the AI-induced bone loss [
100].
Zoledronate is the most extensively investigated intravenous BP in the CTIBL setting, both in pre- and postmenopausal patients. In the bone sub-protocol of the ABCSG-12 trial, 404 premenopausal women were randomised to receive hormone treatment (goserelin + anastrozole vs. goserelin + tamoxifen) with or without zoledronate. After 3 years, patients receiving the BP exhibited stable BMD at both LS and trochanter (+ 0.4 and + 0.8%, respectively), while at 60 months zoledronate treatment was associated with BMD increases at both sites, compared to baseline (4.0% at LS,
p = 0.02; 3.9% at trochanter,
p = 0.07) [
51]. Those who received endocrine therapy alone experienced significant bone loss at both time-points, with the greatest loss being observed in the goserelin + anastrozole arm.
In postmenopausal women undergoing AI therapy, the Z-FAST, ZO-FAST and E-ZO-FAST trials compared upfront zoledronate treatment (4 mg every 6 months) with delayed administration, started after the detection of fractures or BMD decrease. At the final analyses, all these studies showed significantly higher BMD values in the “upfront” arms at LS, FN and hip, as compared to “delayed-treatment” groups [
101‐
103]. In agreement with these data, Wagner-Johnston et al. described that upfront zoledronate addition to letrozole treatment, in postmenopausal patients previously treated with tamoxifen, was less frequently associated with LS BMD decrease as compared to delayed therapy. This difference was statistically significant after 5 years (
p < 0.0001), while there were no significant differences in osteoporosis and fracture occurrence [
104]. A recent study has also described a significant increase in LS BMD (+ 11.6%,
p = 0.01) when zoledronate was given alongside adjuvant AI in women with pre-existing osteopaenia or osteoporosis [
105].
Denosumab has also been investigated for its role in the prevention of AI-induced bone loss. In an initial randomised phase II study, 252 women with early HR + BC were randomised to receive an AI with or without denosumab (60 mg every 6 months for 2 years), and those in the denosumab arm experienced higher BMD gains at multiple sites, compared to controls [
106]. The subsequent ABCSG-18 phase III trial prospectively evaluated the effects of adjuvant denosumab in postmenopausal patients with early HR + BC receiving AIs. A total of 3420 women were randomised to receive either denosumab or placebo every 6 months. Denosumab was associated with a significantly delayed time to first fracture and a reduced fracture incidence, compared to placebo (independently of baseline BMD) [
107]. However, after denosumab discontinuation a rebound effect with accelerated bone loss was described [
108,
109] leading to the proposal of a sequential BP administration to retain BMD values.
Guidelines for the Use of BTAs in BC
Current guidelines recommend adjuvant BTA treatment in those with a baseline
t score < − 2 or at least two risk factors for fractures [
110]. A panel of bone experts representing the major international societies that promote bone health and research (i.e. International Osteoporosis Foundation, IOF; Cancer and Bone Society, CABS; European Calcified Tissue Society, ECTS; International Expert Group for AIBL, IEG; European Society for Clinical and Economics Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, ESCEO; International Menopause Society, IMS) has recently published a position statement that recommends BTA administration also to patients with a baseline
t score < − 1.5 with an additional risk factor for fracture, while those women with a baseline
t score > − 2 and no fracture risk factors should be managed according to the BMD variations which occurred during the first year of AI treatment [
94]. There is no consensus about the optimal treatment duration, but the Cancer Care Ontario (CCO) and American Society of Clinical Oncology (ASCO) guidelines do not recommend the administration of zoledronate for more than 5 years, while clodronate should be given for up to 3 years [
111].
In premenopausal patients undergoing ovarian suppression, 4 mg zoledronate every 6 months is recommended in addition to calcium and vitamin D supplementation. In postmenopausal women, either oral or intravenous BP have proven efficacious in preventing bone loss during AI treatment, and thus the treatment choice should depend upon local guidelines, the different toxicity profiles and concurrent therapies [
49,
70]. Further clinical trials are needed to compare different BP doses and schedules [
111].
Compliance to oral BP should be regularly assessed and, if unsatisfactory, switching to an intravenous BTA should be considered [
94].
A recent prospective study investigated adherence to CTIBL treatment guidelines by both patients and clinicians. Vitamin D and calcium supplementation was prescribed in three quarters of those receiving AIs, but failure to comply with guidelines was identified in 11.6% of cases. A total of 12% (54 of 438 patients) received a BP, but seven patients who were osteoporotic did not receive antiresorptive medication [
112]. These data underline the need for clarification and improved awareness of current guidelines.
There is still a debate about the administration of denosumab in the adjuvant setting; European bone experts suggest that it might be offered at the same dosage administered to patients with osteoporosis [
49], while US clinicians underline the need for more consistent data, before making any recommendation [
111].
Recent evidence suggests that adjuvant BP also reduce bone recurrence and improve survival in postmenopausal patients with BC [
113]. Although the routine use of BP in this setting has not received regulatory approval, bone experts and oncologists recommend their administration to postmenopausal women with intermediate/high risk of BC (T2-4, N1-3, grade 2–3, ER negative or Her2 positive), regardless of BMD values [
110,
111].