Bisphosphonates work effectively to inhibit osteoclast-mediated bone resorption. Bisphosphonates are a first line pharmacotherapy for fracture prevention. The commonly used bisphosphonates in clinical practice include alendronate, ibandronate, risedronate, and zoledronic acid (Table 18.3) [32], of which zoledronic acid is the most potent osteoclast inhibitor and has been by far mostly studied for fracture prevention in breast cancer survivors [33].

Although oral bisphosphonates have been shown to prevent AIBL in several small-scale prospective studies [34–36], high-quality evidence derived from four randomized controlled trials (Z-FAST, ZO-FAST, E-ZO-FAST, ABCSG-12) with more than 2,500 women with breast cancer receiving an AI supports the efficacy of intravenous zoledronic acid (4 mg every 6 months) for prevention of AIBL [37–40]. This benefit was maintained during the long-term follow-up of the ABCSG-12 (94.4 months) [41] and the E-ZO-FAST (36 months) studies [42]. Whether this advantage in BMD preservation translates into a fracture reduction efficacy for zoledronic acid remains unknown, as fracture rates were not a primary outcome and study power was insufficient. Nevertheless, given the strong inverse association between BMD and fracture risk [43], it is reasonable to assume that prevention of AIBL with a bisphosphonate does prevent fractures [44–46].

The optimal time for initiation of bisphosphonate therapy in postmenopausal breast cancer survivors on AI is a subject of debate. Two approaches have been studied on zoledronic acid; an immediate or prophylactic therapy (initiation of zoledronic acid regardless of the baseline BMD status) versus delayed therapy (initiation when a post-baseline BMD T-score reaches a level of <−2.0, or the patient has a fracture). Both the Z-FAST [37] and the N03CC (Alliance) trials [47] have shown that immediate therapy with zoledronic acid was more effective in preventing AIBL after 5 years of follow-up without a significantly higher incidence of adverse events compared with delayed treatment in postmenopausal women receiving letrozole for breast cancer. While the studies were not adequately powered to detect differences in fracture rates, there appears to be a trend toward fewer fractures in women receiving immediate zoledronic acid therapy, with the rib and foot as the most common fracture sites [37]. Current American Society of Clinical Oncology (ASCO) treatment guidelines for maintaining bone health in women with breast cancer are less specific, recommending antiresorptive therapy when T-score ≤−2.5 and individualized therapy if T-score is between −2.5 and −1.0 (Table 18.2) [30]. According to the European Society for Medical Oncology (ESMO) guidelines issued in 2014, patients with cancer receiving chronic endocrine therapy known to accelerate bone loss (e.g., AI, ovarian suppression, or oophorectomy for breast cancer and androgen deprivation therapy for prostate cancer) should receive bisphosphonates along with weight-bearing exercise and vitamin D/calcium supplements, if their T-score is <−2.0 or any two of the following risk factors were identified: age > 65, T-score < −1.5, smoking (current and history of), BMI <24 kg/m², a family history of hip fracture or personal history of fragility fracture above age 50, oral glucocorticoid use for >6 months. No treatment is recommended, except exercise and vitamin D/calcium supplement, if the T-score is >−2.0 with no additional risk factors (Fig. 18.1) [48, 49]. This patient’s T-score was >−2.0, but she had a history of a parental hip fracture and a T-score of <−1.5 which would have qualified her, per the ESMO guideline, for immediate bisphosphonate therapy. Her options include semiannual intravenous injections of 4 mg zoledronic acid, weekly oral 70 mg alendronate, weekly oral 35 mg risedronate, or monthly oral 150 mg ibandronate. BMD needs to be monitored every 1–2 years while a patient is on oral bisphosphonates and individualized for those on IV bisphosphonates (although the 1–2 year time frame is also reasonable) [49]. If patients do not meet the criteria for initiating an antiresorptive treatment, BMD and risk status need to be reassessed at yearly intervals; in the event of annual BMD decrease of ≥5 % using the same DXA machine, secondary causes of bone loss including vitamin D deficiency should be evaluated, and an antiresorptive therapy should be initiated. For patients demonstrating ongoing loss in BMD while on antiresorptive therapy, provided that patient compliance with therapy especially for oral bisphosphonates is first confirmed, a switch to an alternative regimen (from oral to IV) or agent should be considered [28]. Denosumab may be an alternative to bisphosphonates for patients who are either unable to tolerate or fail to respond to trial of bisphosphonate [48–50].

Besides preserving BMD and preventing fractures, emerging evidence indicates that early zoledronic acid therapy may have additional antitumor and antimetastatic effects on the bone of breast cancer women regardless of menopausal status [41, 51]. In the AZURE randomized open-label phase 3 trial, zoledronic acid improved invasive disease-free survival (IDFS) in those who were over 5 years since menopause at trial entry (N = 1041, HR 0.77, 95 % CI 0.63–0.96) but not in all other menopausal groups (premenopause, perimenopause, and unknown status) [51]. A recent large meta-analysis was conducted by Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. It was concluded that adjuvant bisphosphonates (e.g., zolendronic acid, ibandronate, pamidronate, clodronate) reduced the metastatic bone recurrence rate and improved disease-free and overall survival in women with breast cancer; however, these benefits were only observed in women who were postmenopausal when treatment began [52].

Bisphosphonates are contraindicated in patients with a low glomerular filtration rate (GFR < 30 ml/min/1.73 m²), hypocalcemia, or sensitivity to bisphosphonates. In accordance with the US Food and Drug Administration (FDA)-approved labeling, the American Society of Clinical Oncology expert panel recommends that serum creatinine should be tested prior to each dose of zoledronic acid [30]. If unexplained renal dysfunction is identified, defined as an increase in serum creatinine of ≥0.5 mg/dL over baseline or an absolute level of ≥1.4 mg/dL among patients with previously normal baseline serum creatinine levels, discontinuation of zoledronic acid is warranted. These patients should be reassessed monthly, and zoledronic acid should be reinstituted cautiously if the renal function returns to baseline [30]. In the absence of other contraindications, intravenous bisphosphonates can be used in patients with esophageal disease [11]. Further studies are needed to guide decisions about duration of bisphosphonates therapy and drug holidays. Limited data from randomized controlled trials generally suggest that the risk of vertebral fractures is reduced, with the continuation of bisphosphonate therapy beyond 3–5 years [53]. However, consistent evidence of a significant reduction in non-vertebral fracture with bisphosphonate therapy beyond 5 years is lacking [53]. While recommendations for discontinuation of bisphosphonates need to be drug-specific (Table 18.3), in general, drug holidays can be considered for patients who have been persistently on bisphosphonate therapy for 3–5 years and for those who have a stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future [28, 33, 48, 53]. In addition, a healthy lifestyle with weight-bearing exercise and calcium/vitamin D repletion is encouraged if dietary intake is not adequate. Continued bone loss despite adherence to these guidelines suggests an overlooked secondary cause of osteoporosis, poor compliance with recommended therapies, or a true nonresponse to bisphosphonates. A referral to a local metabolic bone expert and consideration of alternative bone protective agents discussed below should be considered in these situations.