Abstract
Estrogen-receptor positive tumours represent the majority of breast cancers in postmenopausal women. Adjuvant endocrine therapy with aromatase inhibitors (AIs), continued for up to 10 years in high-risk patients, reduces by 40% the risk of recurrence. However, this therapy, among other side effects, is burdened with a higher incidence of osteoporotic bone fractures. To date, both bisphosphonates and denosumab are recognized as first-line drugs in the primary prevention of osteoporotic fractures in patients treated with AIs. They have demonstrated their effectiveness in increasing bone mineral density and in reducing the incidence of fractures, but they have also been shown to improve disease free survival (DFS).
Introduction
Endocrine therapy is a milestone in the adjuvant treatment of oestrogen-receptor positive breast cancer, particularly in postmenopausal women. It has been widely demonstrated that adjuvant endocrine therapy reduces the risk of both locoregional and distant recurrence and improves overall survival in oestrogen-receptor positive breast cancer patients [1].
In the last decade, great improvement has been made in adjuvant endocrine therapy in postmenopausal women, such as the spread of the up-front use of aromatase inhibitors (AIs) instead of tamoxifen alone and their sequential use (2–3 years of tamoxifen followed by AIs to year 5) [2]. More recently, many clinical trials have evaluated the extension of adjuvant endocrine treatment in high-risk patients up to 10 years of treatment (extended therapy) [3]. In 2017, a meta-analysis including 11 randomised controlled trials (RCTs) on 29.000 women, has shown that extended therapy was associated with a significant improvement in cancer-specific survival (OR = 0.87; IC 95% 0.79–0.96; p = 0.004) and in disease free survival (DFS) (OR = 0.87; IC 95% 0.75–0.99; p = 0.002), with a reduction in disease recurrence rates (OR = 0.76; IC 95% 0.64–0.90; p = 0.001) and in contralateral breast cancers incidence (OR = 0.74; IC 95% 0.59–0.93; p = 0.008) [4].
Nevertheless, it must be considered that the prolongation of endocrine therapy is burdened, among other side effects, with a higher incidence of osteoporotic bone fractures (femur, hip or others) as shown in a recent meta-analysis including 7 RCTs on 16.349 patients (OR = 1.34, p < 0.001) [5].
Discussion
Bone fractures are not rare among breast cancer postmenopausal patients, as osteoporosis is a common condition in postmenopausal women and bone is the most frequent site of breast cancer metastases. In these patients the incidence of fractures is 40 per 1000 person-years and the mean age at which hip fractures occur is lower than in healthy postmenopausal women (61 years [6] vs 74 years [7]).
AIs are responsible for a 2–4 times higher rate of bone loss in breast cancer postmenopausal patients than physiological postmenopausal women, causing a thinning of both trabecular and cortical bone, leading to a lower bone mineral density and an increased risk of fractures. It has been demonstrated that, in clinical practice, about 18–20% of fractures are attributable to AIs, especially if taken in extended therapy regimens [8]. The ATAC trial has shown that fracture rates increased annually by 2.93% for postmenopausal patients on anastrozole (whereas postmenopausal patients on tamoxifen had an annual fracture rate increase of 1.9%, meaning +55% relative risk of fracture for patients on anastrozole) [9]. Also, Tseng et al. [10] proved an increased fracture risk (pooled RR 1.33; 95% CI 1.21–1.47) in patients under AIs compared with the tamoxifen group.
A systematic review and meta-analysis of 30 RCTs including 117.974 participants showed a RR for all osteoporotic fractures of 1.35 in patients on AI therapy (95% confidence interval [CI], 1.29–1.42; P < 0.001) compared to controls. In particular the risk of osteoporotic fractures was most expressed for vertebral fractures 1.84 (95% CI, 1.36–2.49; P < 0.001) [11].
It follows that the prevention of osteoporosis in breast cancer postmenopausal patients under AIs plays an essential role and requires a specific pharmacological therapy.
For this reason, attention has been paid in the recent years to agents capable of modifying bone metabolism, such as bisphosphonates and denosumab. These drugs exert their action by reducing osteoclastic activity, with the dual effect of reducing bone reabsorption and modifying the bone microenvironment making it less receptive to the implantation of cancer cells.
In fact, the high bone turnover not only increases the risk of fractures, but also facilitates the nesting of cancer cells with the formation of the so-called “premetastatic niche [12]”, set in the endosteal niche that lines the trabecular and endocortical bone surface [13].
Bisphosphonates are synthetic compounds capable of attaching themselves to the bone surface, thus blocking osteoclastic activity. Some researchers suggest that bisphosphonates might also have antitumor effect, through the inhibition of angiogenesis, tumour-cell invasion, and adhesion in bone and some immunomodulatory effects [14]. Common side effects are those affecting the gastrointestinal tract, but they can be easily controlled with weekly formulations and adequate methods of intake, while the risk of osteonecrosis of the jaw remains very low [15].
Denosumab is a human monoclonal antibody directed against RANK-L which can determine a selective block of osteoclasts activity with a uniform efficacy on the whole skeleton, regardless of bone turnover, resulting in the inhibition of osteoclastic resorption of the cortical bone [16].
In 2015, the EBCTCG meta-analysis, analysed the data of 18766 patients and concluded that adjuvant bisphosphonate treatment can reduce breast cancer recurrence rates in bone and improve breast cancer survival, but a clear benefit was demonstrated only in postmenopausal women, irrespective of ER status or grade of the primary tumor, axillary lymph-node status, previous chemotherapy or others [17]. Their use in clinical practice in this group of patients is therefore recommended [12].
The Cochrane’s latest systematic review about the use of bisphosphonates in breast cancer postmenopausal patients (under either AIs or tamoxifen) analysed the results from 11 RCTs and has shown a reduced risk of bone metastases and a significant survival improvement in women treated with these agents versus placebo (HR 0.77, 95% CI 0.66 to 0.90; p = 0.001) [18].
Efficacy and safety of denosumab have been evaluated in two studies on women with non-metastatic breast cancer treated with AIs. The former shown that denosumab significantly increased bone mineral density at 2 years in different skeletal sites compared to placebo (+7.6% lumbar spine, 4.7% total femur, 3.6% at the femoral neck, 5.9% at the trochanter level, 6.1% at the distal third of the radius and 4.2% overall; for all: p < 0.0001) [19]. The latter, the ABCSG-18 study published in 2015, showed a significant reduction in the incidence of vertebral fractures (OR 0.53; 95% CI 0.33–0.85, p = 0.009), a significant delay in time from randomisation to first clinical fracture (HR 0.44; 95% CI 0.31–0.64, p < 0.0001) [20] and a significant improvement of DFS for denosumab versus placebo (HR 0.82; 95% CI 0.69–0.98, p = 0.026). However, a detailed analysis of the study has shown that most of the observed benefit on DFS derived from a reduction in the incidence of non-mammary primitives and in death as a first event.
In D-CARE study, 4509 women were randomly assigned to receive denosumab (n = 2256) or placebo (n = 2253). The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0.97, 95% CI 0.82–1.14; p = 0.70) [21].
Updated results from del ABCSG-18 study published in 2019 [22] and November 2022 [23] showed an absolute 9-year DFS benefit of 3.5% points (79.4 vs. 75.9%) in the denosumab vs placebo group. Also, bone metastasis free survival and OS improved in the denosumab group (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00 and 90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01 respectively).
Compared to bisphosphonates, denosumab has shown a better tolerability and a better adherence-to-treatment profile. Contrary to D-CARE results on osteonecrosis of the jaw (5% of cases in the denosumab group vs <1% in the placebo group), in long-term outcome analysis of ABCSG-18 study, confirmed no case of mandibular osteonecrosis; moreover, the rate of adverse events in the denosumab group did not significantly differ from that of the placebo group [22,23].
To date, there is no definitive evidence about the duration of the treatment [24], although different guidelines agree in suggesting stopping denosumab at the end of adjuvant endocrine therapy, after careful clinical evaluation of the patient [17,25]. Some studies have highlighted the risk of rebound effect at the end of treatment with denosumab and have therefore suggested setting up a sequential bisphosphonate treatment after its discontinuation before definitive suspension. This strategy seems to slow down the loss in bone mineral density observed in those patients who discontinue denosumab; [26] a single infusion of Zoledronate 5 mg could be useful for this purpose [27] as well as the use of oral bisphosphonates (alendronate) for at least 1–2 years after denosumab suspension [28].
Conclusions
To date, both bisphosphonates and denosumab are recognized as fist-line drugs in the primary prevention of osteoporotic bone fractures in breast cancer postmenopausal patients treated with AIs, as they have demonstrated effectiveness in increasing bone mineral density and reducing the incidence of fractures. Moreover, these drugs have also been shown to improve DFS in breast cancer patients, but, to date, they cannot be prescribed with the sole “adjuvant” intent of improving DFS.
For the first time, the St. Gallen International Consensus Guidelines of 2019 have recommended to introduce the routine use of bisphosphonates in the adjuvant therapy of postmenopausal women [29].
In fact, it has been estimated that adding a bone modifying agent to adjuvant therapy can reduce the risk of recurrence by 18%, the same relative risk reduction than the one achieved by starting upfront AIs instead of Tamoxifen in postmenopausal patients [30].
Should we start considering the association of these agents to adjuvant endocrine therapy the standard of care for postmenopausal women?
Funding information
This research received no external funding.