**4. Current date and use of bisphosphonates**

### **4.1 Zoledronic acid and mode of action**

Zoledronic acid is one of the nitrogen-containing antiresorptive agents, which inhibits osteoclast proliferation. Owing to the chemical similarity to inorganic pyrophosphate, zoledronic acid (and other bisphosphonates) attaches to hydroxyapatite binding sites on the osseous extracellular matrix [2, 15, 16]. The exact mechanism of apoptosis induction in osteoclasts is not fully understood. However, animal experiments have suggested that zoledronic acid inhibits specific transferases, such as geranyl transferase I inhibitor (GGTI-298), leading to loss of protein prenylation in osteoclasts, disrupting their cytoskeleton and inducing programmed death [15, 17, 18]. The main effect is reduced bone resorption, which allows for more time for bone formation and remodeling [9, 19]. It has also been hypothesized that zoledronic acid might stimulate osteoblastic differentiation and bone mineralization. Zoledronic acid seems to have the highest potential among bisphosphonates, because of its high affinity to bone, especially bones undergoing active resorption and increased turnover, such as in malignant processes [20].

### **4.2 Current guidelines and data on bisphosphonates**

Current NCCN guidelines recommend adjuvant bisphosphonate therapy for 3–5 years in the case of menopausal patients with early stages of breast cancer, as well as in patients who recently went through menopause and who are under treatment with GnRH-A and aromatase inhibitors. In daily clinical routine, many oncologists use zoledronic acid [21].

The recently published Southwest Oncology Group (SWOG) S0307 trial was a randomized three-arm trial including more than 6000 patients, aiming to assess differences in zoledronic acid, oral clodronate, and oral ibandronate therapies. No significant difference in disease-free survival and overall survival for the three drugs was found. Authors concluded that oral bisphosphonates could be a valid option with regards to osteo-oncologic treatment [22].

In a 2017 published Cochrane analysis, data collected from more than 37,000 patients were also able to demonstrate the benefits of bisphosphonate therapy. This showed a clear survival benefit with addition of bisphosphonates for postmenopausal patients (HR 0.77, 95% CI 0.66–0.90; p = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity), but not for premenopausal patients (HR 1.03, 95% CI 0.86–1.22; p = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity) [5].

In conclusion, for women with early breast cancer, bisphosphonates were able to reduce the risk of bone metastases and provide an overall survival benefit compared to the placebo or no bisphosphonates group. There is preliminary evidence suggesting that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate.

The Early Breast Cancer Clinical Trials Group (EBCCTG) designed a meta-analysis incorporating data from more than 18,000 women, derived from 26 randomized adjuvant bisphosphonate trials in breast cancer. In postmenopausal patients, there was a statistically significant reductions in the 10 years recurrence rate, (RR = 0.72, 95%, CI = 0.60–0.86, 6.6% vs. 8.8%; two-sided Pp = .0002), as well as in the breast cancer mortality rate (RR = 0.82, 95% CI = 0.73–0.93, 14.7% vs. 18.0%; two-sided p = .002) with the addition of bisphosphonates. The reduction was independent of choice of bisphosphonate therapy, estrogen receptor expression status, axillary lymph node involvement, or use of adjuvant chemotherapy [10].
