Use of osteoclast inhibitors in early breast cancer

INTRODUCTION — Breast cancer is the most common female cancer worldwide. The prognosis of fully treated early breast cancer is usually very good, in part due to systemic therapies reducing the risk of recurrence. For example, in the United States, estimates are that approximately 90 percent of patients will survive five years or more following their initial diagnosis [1]. Therefore, the long-term toxicities of breast cancer therapies need to be considered. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer".)

Systemic therapies used to treat early breast cancer can be associated with loss of bone mineral density (BMD) and increased risk of osteoporotic fractures [2]. Recent international guidelines outline managing bone in the setting of breast cancer [3,4]. Bisphosphonates and denosumab are potent inhibitors of osteoclast activity. They are US Food and Drug Administration approved for managing osteoporosis and bone metastases from a variety of malignancies. They aid in treating therapy-related bone loss and complement nutritional (calcium and vitamin D), exercise, and healthy lifestyle behaviors. They have also been evaluated as adjuvant treatments in breast cancer.

This topic will review the use of bisphosphonates and denosumab for bone health and their impact on breast cancer outcomes in the adjuvant setting.

Methods to assess risk of fracture (eg, using history, physical exam, algorithms such as the fracture risk assessment tool [FRAX]), imaging BMD, and optimal intake of calcium and vitamin D are discussed elsewhere.

●(See "Osteoporotic fracture risk assessment".)

●(See "Screening for osteoporosis in postmenopausal women and men".)

●(See "Calcium and vitamin D supplementation in osteoporosis".)

●(See "Evaluation and treatment of premenopausal osteoporosis".)

●(See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

●(See "Evaluation and treatment of premenopausal osteoporosis".)

Additionally, the utility of osteoclast inhibitors in the management of bone metastases from breast and other cancers is reviewed elsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

In this topic, we will use the terms "woman/en" or "patient" to describe genetic females. However, we recognize that not all people with breasts identify as female, and we encourage the reader to consider transgender and gender nonbinary individuals as part of this larger group.

The American Society of Clinical Oncology guideline on the management of male breast cancer addresses bone-modifying agents for this population [5].

TREATMENT FOR BREAST CANCER THERAPY-ASSOCIATED BONE LOSS — This section is specific to osteoporosis prevention and treatment. Osteoclast inhibitor therapy as adjuvant anticancer therapy is discussed in a separate section. (See 'Choice of bisphosphonate for anticancer therapy' below.)

Risk factors — Women with a history of breast cancer may be at increased risk of osteoporosis and fracture secondary to anticancer therapies administered [3,4]. Osteoporosis is associated with an increased risk of fracture and can be associated with significant morbidity, mortality, disfigurement, and loss of self-esteem, as well as health care expenditure [6].

Estrogen is an important hormone for bone homeostasis in women and it is an important target for hormone receptor-positive breast cancer, for which antiestrogen therapies are used. Therefore, anticancer therapies that decrease circulating estrogen levels or estrogen signaling may be associated with a negative impact on bone by decreasing bone mineral density (BMD) and increasing risk of osteoporotic fractures.

Adjuvant systemic therapies for breast cancer that are associated with an increased risk for bone loss include [3,4]:

●Antiestrogen treatments (chemical or surgical ovarian ablation, aromatase inhibition (AI), and in premenopausal patients, tamoxifen)

●Chemotherapies that promote premature ovarian dysfunction

●Supportive medications, such as glucocorticoids

By contrast, the use of tamoxifen provides protection against bone density loss in postmenopausal women. However, tamoxifen is associated with accelerated loss of bone mass in premenopausal women [7]. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Tamoxifen'.)

General measures — The foundation of bone health involves optimizing calcium and vitamin D intake, use of weight-bearing exercises, and limiting or removing bone-offending medications and behaviors, such as tobacco use [4]. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Lifestyle measures to reduce bone loss'.)

Screening and indications for pharmacologic therapy — Screening for bone loss among women with a history of breast cancer includes a detailed history, physical exam, and medication review. Some women should also be screened with dual-energy x-ray absorptiometry (DXA) or another tool that reliably assesses the risk of fragility fracture. (See "Approach to the patient following treatment for breast cancer", section on 'Evaluation of bone density'.)

Indications for pharmacologic therapy for bone health are the same for women with a history of breast cancer as for the general population and are discussed elsewhere. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection'.)

Premenopausal women — Although less than one-third of newly diagnosed breast cancer cases occur in premenopausal women, the risk of long-term bone-related toxicity as a consequence of cancer-related therapy is of unique concern, primarily because of patients' anticipated long life expectancy [1]. Breast cancer therapy-induced bone loss in premenopausal women may occur due to ovarian dysfunction secondary to chemotherapy, or endocrine treatment (gonadotropin-releasing hormone agonists) or oophorectomy, as well as due to oral antiestrogen therapies. The risk of chemotherapy-induced ovarian dysfunction and associated bone loss is impacted by the patient's age at time of therapy and the chemotherapy regimen used. Note that the risk of accelerated bone loss with ovarian dysfunction may not be permanent; some women with chemotherapy-induced amenorrhea will experience resumption of menses during follow-up, which may allow BMD to improve, although it may not return to baseline [8]. (See "Overview of side effects of chemotherapy for early-stage breast cancer", section on 'Chemotherapy-induced amenorrhea'.)

Among premenopausal women treated with chemotherapy, the rate of BMD loss may approach 3 to 8 percent at the lumbar spine within 12 months of initiating chemotherapy [9-12]. BMD loss may occur in premenopausal women as a result of adjuvant tamoxifen [8,13,14], or use of ovarian suppression (chemical or surgical) [13,15]. Retrospective data suggest that at five years both adjuvant chemotherapy and biochemically induced menopause with GnRH therapy have a similar impact on loss of BMD [16]. However, the cumulative loss of BMD due to cancer therapy-induced menopause, which occurs acutely, versus BMD loss in natural menopause, which proceeds over years, has not been formally studied. In addition, the fracture risk attributable to these changes in BMD has not been quantified. Finally, it is unclear whether entering menopause by any particular mode ultimately has a greater lifetime impact on fracture.

The evaluation and treatment of women at risk for premenopausal osteoporosis is discussed in more detail separately. (See "Evaluation and treatment of premenopausal osteoporosis" and "Osteoporotic fracture risk assessment", section on 'Clinical risk factor assessment'.)

Bisphosphonates — When a pharmacologic intervention is indicated to reduce the risk of osteoporosis or fracture (eg, T score of -2.5 or lower on a DXA scan or a history of fracture due to low BMD), then a bisphosphonate is the drug class of choice in premenopausal women with a history of breast cancer [17-19].

Bisphosphonate therapy in premenopausal women with chemotherapy-induced ovarian failure and/or ovarian suppression may preserve or improve BMD, but whether it decreases fractures is not clearly defined [17-19].

It is of note that bisphosphonates may leach from bone over time and can cross the placenta. Hence, the bisphosphonates are classified as at risk for fetal harm, and women of childbearing potential should be advised of this risk, which may persist after discontinuation. The bisphosphonates that are US Food and Drug Administration (FDA)-approved for osteoporosis prevention or treatment do not have an indication specific to premenopausal women. If bisphosphonate use is indicated and the woman is of childbearing potential, consideration should be given to using a multidisciplinary approach to decision-making (obstetrics, endocrinology, oncology). For women of childbearing potential who may hold anti-estrogen therapy in order to pursue pregnancy, the impact on bone mineral density and fracture risk has not been studied. Further discussion of breast cancer and pregnancy, and of use of antiresorptive agents during pregnancy, is found elsewhere. (See "Gestational breast cancer: Treatment" and "Evaluation and treatment of premenopausal osteoporosis".)

Is there a preferred agent for osteoporosis in premenopausal patients with early breast cancer? — For premenopausal patients with indications for a pharmacologic intervention to preserve bone mass and decrease the risk of osteoporotic fracture, data from small trials are available to support the use of various bisphosphonates (eg, clodronate, risedronate, pamidronate, and zoledronic acid) in the management of bone loss from cancer treatment-related amenorrhea [12,20-22].Denosumab (60 mg subcutaneously every six months) is not labeled for use in premenopausal women.

Data illustrating a positive impact on BMD in young women with breast cancer include the CALGB trial 79809. Among 150 premenopausal women with stage I to III breast cancer who had chemotherapy-induced ovarian failure, those assigned to zoledronic acid experienced increases in lumbar spine BMD at one year, versus those who had been observed during this time period (a 1.2 percent gain versus a 6.7 percent loss) [23]. The majority of zoledronic acid-related toxicities were mild (grade 1/2); grade 3 toxicities included fatigue, arthralgias, and bone pain in 1, 2, and 8 percent of women, respectively. There were no cases of osteonecrosis of the jaw or serious renal toxicity.

Similar results were seen in a substudy of the ABCSG-12 trial, in which zoledronic acid stabilized BMD in premenopausal women receiving adjuvant goserelin and either tamoxifen or anastrozole [15,24]. These data are discussed in more detail elsewhere. (See "Evaluation and management of aromatase inhibitor-induced bone loss", section on 'Bone mineral density'.)

Postmenopausal women — Postmenopausal women with breast cancer may have a baseline risk of osteoporosis due to age and sex [25,26]. Data generated from the WHI-OS study demonstrated that women with a history of breast cancer diagnosed after the age of 55 have a higher risk of fractures than that of those without a history of breast cancer [27].

Chemotherapy and its associated supportive therapies may have a negative effect on BMD, although the direct effects of chemotherapy on the BMD of this population are not well established. Preliminary data suggest that women receiving adjuvant chemotherapy but not endocrine therapy may lose 1 to 10 percent of their bone mass within one year of chemotherapy [28].

While adjuvant tamoxifen in postmenopausal women can promote stabilization to mild increase in bone mass, most likely secondary to the end-organ specificity of this selective estrogen receptor modulator [14,29], endocrine therapy with an AI is associated with loss of BMD. Other risk factors for osteoporosis, as they relate to women with or without a history of breast cancer, are discussed elsewhere. (See "Osteoporotic fracture risk assessment", section on 'Clinical risk factor assessment'.)

Bisphosphonates and anti-RANK-ligand — Interventions with a bisphosphonate or denosumab may be indicated to preserve bone mass and reduce risk of osteoporotic fractures in postmenopausal women treated for breast cancer [3,4,30,31]. This is of special relevance for women treated with an AI as they may experience a two- to fourfold increase in the rate of bone loss over the expected physiologic rate [31].

In several randomized trials, bisphosphonates prevented or reduced bone loss in women receiving AIs, but none of the trials were designed or powered to assess fractures as a primary outcome. These data are discussed elsewhere. (See "Evaluation and management of aromatase inhibitor-induced bone loss", section on 'Bisphosphonates'.)

Denosumab has also been shown to improve BMD in women receiving AIs, and has also been shown to reduce the risk of clinical fractures compared with placebo (but it has not been compared with bisphosphonates). These data are discussed elsewhere. (See "Evaluation and management of aromatase inhibitor-induced bone loss", section on 'Denosumab'.)

Data regarding denosumab for osteoporosis among the general population are discussed elsewhere.

Denosumab has been associated with an increased risk for vertebral fractures after discontinuation. Strategies to address this risk are discussed elsewhere and include use of a bisphosphonate upon stopping denosumab [32,33]. The optimal management of bone health after denosumab exposure continues to be an area of investigation. (See "Denosumab for osteoporosis", section on 'Increased vertebral fractures' and "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy'.)

Is there a preferred agent for prevention and treatment of osteoporosis in postmenopausal patients with early breast cancer? — For postmenopausal patients who warrant a pharmacologic intervention to preserve bone mass and decrease the risk of osteoporotic fracture, any one of several oral or intravenous bisphosphonates, or denosumab, may be used. This approach is discussed in more detail elsewhere. (See "Denosumab for osteoporosis" and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Selection of oral bisphosphonate (usually preferred)'.)

Agents typically not used for osteoporosis in those with early-stage breast cancer

Exogenous estrogens — Hormonal therapies are generally avoided in patients with hormonally driven cancers [4]. Other classes of drugs to prevent or treat osteoporosis are favored.

Parathyroid hormone — Teriparatide (parathyroid hormone [PTH] 1-34) and abaloparatide (PTH-related protein [PTHrP] 1-34) are anabolic osteoporosis agents that increase bone formation. However, teriparatide and abaloparatide are generally not favored for used in breast cancer. The FDA label of both PTH products warns that patients with bone metastases or prior radiation therapy should not be treated with these therapies. Although there are no known bone metastases when treating in the adjuvant setting, women with early-stage breast cancer are at risk of occult bone metastases and may have occult disseminated tumor cells within the bone marrow. There is theoretical concern that the PTH stimulation may promote growth of breast cancer cells in the bone microenvironment [34,35]. In addition, therapy with either PTH agents raises concern for risk of osteosarcoma [36,37]. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Long-term risks'.)

Romosozumab is another anabolic osteoporosis agent. It is a humanized monoclonal antibody that binds to sclerostin but does not have safety data in women with a history of breast cancer. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Romosozumab'.)

ADJUVANT BONE-MODIFYING TREATMENT FOR HIGHER-RISK BREAST CANCERS

Bisphosphonates for anticancer therapy

Efficacy — In an EBCTCG patient-level meta-analysis of 26 clinical trials, treatment with bisphosphonates (alendronate, clodronate, ibandronate, pamidronate, risedronate, or zoledronic acid) led to borderline significance in improvements in recurrence, distant recurrence, and breast cancer mortality in postmenopausal women with early-stage breast cancer. The reduction in bone recurrence was modest but more definite (7.8 versus 9.0 percent; relative risk 0.83, 95% CI 0.73-0.94). Among postmenopausal women, bisphosphonate treatment resulted in statistically significant reductions in bone recurrence (6.6 versus 8.8 percent), fracture rates (0.1 versus 10.3 percent), breast cancer mortality (14.7 versus 18.0 percent) and overall survival (OS; 21.1 versus 23.5 percent) [38]. These benefits were not observed among premenopausal women. Most patients in this meta-analysis (83 percent) had received adjuvant chemotherapy, and bisphosphonate treatment was initiated shortly after surgery or chemotherapy.

Similar findings were seen in subsequent meta-analyses [39,40]. Other studies have shown mixed results [41-43], for example one meta-analysis failing to show statistically significant improvements in breast cancer recurrence or breast cancer mortality [41], and another demonstrating improvements in OS and fracture risk but not frequency of bone metastases or progression-free survival [42].

These data have impacted guideline recommendations for postmenopausal women with early-stage breast cancer [3,44]. However, universal use of adjuvant bisphosphonate therapy in postmenopausal women with early stage breast cancer has been questioned. Indeed, thought leaders have proposed adjuvant bisphosphonate use be reserved only for those postmenopausal women with a very high risk for recurrence [45].

Patient selection — For postmenopausal women (naturally, surgically, or chemically induced) with a moderate to high risk of distant recurrence (10 percent or higher) receiving any form of adjuvant systemic therapy, we suggest adjuvant bisphosphonates (algorithm 1). Although there are clear indications for osteoclast inhibitors for those with decreased bone mineral density and risk for fracture [3,4,17,30], their value in improving breast cancer outcomes and their acceptance for this use by clinicians and patients continues to evolve [46-48].

In weighing the pros and cons of adjuvant bisphosphonate therapy with the patient, factors to consider include the overall risk of breast cancer recurrence, the risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy [44]. Although the data do not yet provide a means to identify those most likely to benefit from adjuvant bisphosphonate therapy, some experts have expressed the view that therapy should be reserved for those considered to be at high risk of breast cancer recurrence (10 percent or higher) [45,47,49,50]. The online tool, NHS PREDICT, can help estimate the potential benefit from the use of an adjuvant bisphosphonate.

We note that the data in support of adjuvant bisphosphonates were generated using subset analysis, the biologic mechanism by which this subset benefits is not yet defined, and that the absolute anticancer benefits of adjuvant bisphosphonate therapy are likely to be small (meta-analyses have suggested an approximate 2 to 3 percent breast cancer mortality benefit [38,51,52]). As such, some patients or clinicians may reasonably opt not to consider this treatment given the potential for toxicity and concerns about modest efficacy.

Choice of bisphosphonate for anticancer therapy — Different osteoclast inhibitors are available worldwide, including oral and intravenous (IV) formulations (algorithm 1). When an adjuvant bisphosphonate is indicated, we suggest zoledronic acid or clodronate (although clodronate is not available in the United States), and consider oral ibandronate a less favored option (as there are no direct data supporting a disease-free survival (DFS) benefit with this agent). However, available data suggest that there are no survival advantages associated with one of these bisphosphonates over another [44,53]. There is insufficient evidence to support adjuvant alendronate or risedronate in regards to their potential anticancer efficacy. Access to adjuvant bisphosphonate therapy may limit the choice of therapy. (See 'Dosing and duration' below.)

In SWOG 0307, over 6000 women with stage I to III breast cancer (58 percent of whom were post-menopausal or over 50 years) who were treated with adjuvant systemic therapy were randomly assigned to clodronate (1600 mg orally) or ibandronate (50 mg orally) daily for three years, or zoledronic acid (4 mg IV every month for six months then every three months for 2.5 years) [53]. Five-year DFS rates were similar in each arm (88, 88, and 87 percent for clodronate, zoledronic acid, and ibandronate, respectively), with OS rates of 93 percent in the zoledronic acid and ibandronate arms and 92 percent in the clodronate arm. Ibandronate led to more grade 3/4 toxicities compared with either clodronate or zoledronic acid (10.5 versus 8 and 9 percent, respectively), but zoledronic acid resulted in higher rates of osteonecrosis of the jaw relative to ibandronate and clodronate (1.3 versus 0.8 and 0.4 percent, respectively). Notably, prior to treatment assignment, an overwhelming majority of patients (73 percent) indicated a preference for oral therapy rather than IV treatment if the agents were equally efficacious.

While SWOG 0307 demonstrated similar DFS between clodronate, ibandronate, and zoledronic acid, two separate trials evaluating ibandronate versus control have not demonstrated DFS benefits with oral ibandronate versus control either in postmenopausal women (GAIN/TEAM-IIB) [43,54] or in premenopausal patients (GAIN) [54]. Thus, when considering which adjuvant bisphosphonate to use, ibandronate does not have direct evidence to support impacting DFS and is the least favored option.

Dosing and duration — When an adjuvant bisphosphonate is to be used, the strongest data are in clodronate and zoledronic acid. In our practice, we only have access to zoledronic acid. Zoledronic acid 4 mg IV is started within the typical adjuvant window that ranges from neoadjuvant therapy into three to six months after surgery. This is consistent with expert guidelines that support early initiation of bisphosphonate therapy [44].

As with bisphosphonate therapy for any indication, pretherapy attention is to be paid to oral health, electrolytes, and organ function, with particular attention to renal and gastrointestinal function, pending the route of bisphosphonate administration.

Guidelines from expert groups generally favor the incorporation of adjuvant bisphosphonates at higher doses than typical osteoporosis treatment. As examples:

●A consensus guideline from a European panel recommends the use of zoledronic acid 4 mg IV every six months or clodronate 1600 mg orally daily for three to five years in premenopausal women on adjuvant ovarian suppression and postmenopausal women at intermediate or high risk of recurrence [55].

●The American Society of Clinical Oncology (ASCO)-Ontario Health (OH, Cancer Care Ontario [CCO]) Clinical Practice Guideline advises the clinician to consider, when available, the use of either zoledronic acid 4 mg IV every six months or clodronate 1600 mg daily orally as adjuvant therapy for postmenopausal women deemed candidates for systemic adjuvant therapy [51]. The ASCO-OH (CCO) adds the options of zoledronic acid 4 mg every three months for two years, or ibandronate 50 mg daily for three years.

●Guidelines from the European Society of Medical Oncology (ESMO) suggest that zoledronic acid 4 mg IV be used with chemotherapy, followed by either zoledronic acid or daily oral ibandronate or clodronate until 36 months [3].

●The National Comprehensive Cancer Network (NCCN) does not specify details of any particular regimen but notes that for risk reduction of distant metastasis consideration should be given to adjuvant bisphosphonate therapy for three to five years in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive tumors [56].

Zoledronic acid dosed at 4 mg has been investigated in a range of regimens in the adjuvant breast cancer setting. As examples of studies evaluating deintensified strategies:

●The SUCCESS A trial investigated two different regimens of adjuvant zoledronic acid [57]. The study included 2987 patients with early breast cancer, treated with two years of zoledronic acid 4 mg dosed every three months or a total of five years of zoledronic acid 4 mg, dosed initially every three months for the first two years followed by every six months dosing for the next three years. The two arms resulted in similar DFS (hazard ratio [HR] 0.97) and OS (HR 0.98) at a median of five years of follow-up [57]. Adverse events were more frequent in the five-year group (46 versus 27 percent). (See 'Toxicity associated with osteoclast inhibitors' below.)

It has been noted that the SUCCESS A accrual was smaller than planned for this study and follow-up time was short. Nevertheless, the ASCO-OH (CCO) 2022 adjuvant bone modifying agent guideline update included the option of zoledronic acid 4 mg every three months for two years. In the SUCCESS A trial the shorter regimen treated for a total of 32 mg of zoledronic acid over two years versus the longer regimen which treated for a total of 56 mg of zoledronic acid over five years. These data suggest that a shorter duration of therapy, as well as a lower total dose of zoledronic acid was efficacious. A sub-study of the ABCSG-12 trial [58], analyzed whether the number of zoledronate infusions had an impact on breast cancer-specific outcomes and demonstrated no statistically significant difference in DFS or OS between those treated with six or less doses of zoledronic acid from those who were treated with seven or more doses of zoledronic acid. There is interest from both patients and providers to conduct studies with de-escalation of dosing [47,48].

●Similarly, in a substudy of a randomized trial (ABCSG-12), there was no statistically significant difference in DFS or OS in the patients who received ≤6 zoledronate infusions compared with those who received ≥7 zoledronate infusions [58].

The use of adjuvant bisphosphonates (either adjuvant zoledronic acid 4 mg IV or clodronate 1600 mg daily) may be logistically challenging because neither of these regimens is approved by the US Food and Drug Administration as an adjuvant cancer therapy.

Some have advocated that if a well-studied adjuvant bisphosphonate regimen is not accessible, then consideration may be given for the use of osteoporosis dosing of adjuvant bisphosphonates in postmenopausal women with a 10 percent or greater risk of distant recurrence [49]. It is of note that the EBCTCG meta-analysis did not identify a significant difference between dosing regimens or dosing frequency; however, there were insufficient numbers for assessment of osteoporosis dosing efficacy [38].

Denosumab for anticancer therapy — There are mixed data for efficacy of adjuvant denosumab in regards to improving DFS. However, because phase III trials suggest different outcomes in regards to DFS, and no trial has shown an OS benefit, we do not presently utilize denosumab for indications other than prevention or treatment of osteoporosis [44,52,59]. A more detailed review of denosumab for the management of aromatase inhibitor (AI)-induced bone loss is discussed separately. (See "Evaluation and management of aromatase inhibitor-induced bone loss" and "Evaluation and management of aromatase inhibitor-induced bone loss", section on 'Denosumab'.)

The D-CARE trial enrolled 4500 patients with early-stage breast cancer (over one-half of whom were on AIs for hormone receptor-positive disease). The study drug was dosed as denosumab at 120 mg or matching placebo monthly for six months, then every three months for up to five years. Denosumab was associated with neither a bone metastasis-free benefit (HR 0.97 for denosumab versus placebo, respectively; 95% CI 0.82-1.14), nor a DFS benefit (HR 1.04, 95% CI 0.91-1.19) [59,60]. None of the subgroups identified (eg, premenopausal, postmenopausal, hormone receptor-positive or negative disease) experienced benefits in these outcomes. The frequency of osteonecrosis of the jaw was higher among those receiving denosumab (5.4 versus 0.2 percent, respectively), as were atypical femur fractures, though the rates were low in both groups (0.4 versus 0.0 percent, respectively).

The ABCSG-18 trial assessed DFS in 3400 postmenopausal women on AIs for hormone receptor-positive breast cancer randomly assigned to denosumab 60 mg every six months or placebo. The primary endpoint of the study was clinical fracture. Secondary endpoints of this study include disease-related outcomes. At a median follow-up of six years, denosumab was associated with improved DFS (287 versus 240 DFS events; HR 0.82, 95% CI 0.69-0.98) [52]. With longer follow-up (median eight years), denosumab resulted in a 3.5 percent improvement in nine-year DFS (79.4 versus 75.9 percent, HR 0.83, 95% CI 0.71-0.97) [61]. Bone metastasis free survival was 89 versus 86 percent (HR 0.81, 95% CI 0.65-1.00) and OS was 91 versus 90 percent, respectively (HR 0.80, 95% CI 0.64-1.01), but these differences were not statistically significant. There were no cases of osteonecrosis of the jaw and one potential case of an atypical femoral fracture.

At present, ASCO–OH (CCO), ESMO, and NCCN do not provide recommendations for use of adjuvant denosumab as an anticancer intervention.

Use of denosumab for therapy-related bone loss is discussed above. (See 'Bisphosphonates and anti-RANK-ligand' above.)

TOXICITY ASSOCIATED WITH OSTEOCLAST INHIBITORS — Therapy with an osteoclast inhibitor, whether for osteoporosis management or as an adjuvant therapy is generally well tolerated. However, both the bisphosphonates and denosumab are associated with the risk of developing electrolyte disturbance (most notably hypocalcemia), atypical fractures, and osteonecrosis of the jaw or atypical fracture of the jaw.

The intravenous bisphosphonates also may associate with acute phase reactions, renal toxicity, and rarely, ocular inflammation [62], while the oral bisphosphonates may have gastrointestinal side effects. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Osteoclast inhibitor therapy' and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Risks of bisphosphonate therapy in patients with osteoporosis".)

Denosumab may specifically associate with infection and dermatologic reactions. Denosumab, upon discontinuation, may be associated with an increased risk of vertebral fracture, and means to reduce this risk are under investigation [32,63]. This is discussed in detail elsewhere. (See "Denosumab for osteoporosis", section on 'Increased vertebral fractures' and "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy'.)

The incidence of osteonecrosis of the jaw with bisphosphonates or denosumab for osteoporosis treatment or prevention, as well as adjuvant anticancer therapy, appears to be uncommon. With the bisphosphonate studies, the incidence is approximately 0.7 percent [64,65]. A joint guideline from multiple expert groups provides recommendations on oral care and reducing the risk of osteonecrosis of the jaw [66]. Further discussion on the risks of therapy and recommendations for monitoring are provided separately. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw'.)

Of particular importance to premenopausal women are the safety data regarding future pregnancy after bisphosphonate, as the drug may leach from bone over time. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Antiresorptive therapy with bisphosphonates'.)

CAUTION IS TO BE TAKEN IN WOMEN WITH A HISTORY OF BREAST CANCER — It is of note that not all pharmacologic interventions available for management of bone health are appropriate for patients with a history of breast cancer. In general, the estrogen-like, estrogen-progesterone, and parathyroid hormone therapies are not favored in patients with a history of breast cancer as there is theoretical concern regarding the potential to stimulate growth of occult tumor cells and to negatively impact cancer outcomes [4,33,67-69]. The sclerostin-targeting therapy, romosozumab, does not have safety data specific to the breast cancer population.

All drugs used in patients of childbearing potential need to be considered for safety if family planning and lactation has not been completed.

The selective estrogen receptor modulators, such as tamoxifen or raloxifene, are generally not to be used concurrently with an aromatase inhibitor (AI) in a patient with estrogen receptor-positive breast cancer since the combined use of tamoxifen and an AI was not better than tamoxifen alone, in regards to breast cancer outcomes, in a randomized trial [70].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction – Osteoclast inhibitors reduce the risk of osteoporosis and fractures. They have also been evaluated as anticancer treatments in the adjuvant setting to improve breast cancer outcomes. (See 'Introduction' above.)

●General measures – Breast cancer therapy-related bone loss prevention and treatment of osteoporosis and osteopenia should be addressed initially with adequate nutrition (calcium and vitamin D), regular weight-bearing exercise, and healthy lifestyle behaviors. Those at higher risk of osteoporosis and fracture may be candidates for therapy with a bisphosphonate or denosumab. (See 'General measures' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Lifestyle measures to reduce bone loss' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection'.)

●Causes of bone loss in patients with breast cancer – Bone loss may be accelerated in premenopausal women secondary to factors that decrease ovarian estrogen, such as oophorectomy, chemotherapy-induced ovarian dysfunction, or with ovarian suppression due to adjuvant endocrine therapy (eg, gonadotropin-releasing hormone agonists). Accelerated bone loss may occur in postmenopausal women treated with an aromatase inhibitor. Tamoxifen with its agonist-antagonist effects is associated with bone mineral density (BMD) loss in premenopausal women and BMD stability or gain in postmenopausal women. (See 'Treatment for breast cancer therapy-associated bone loss' above.)

●Screening and risk assessment for bone loss – Screening for fracture risk includes history, physical exam, and, in some cases, dual-energy x-ray absorptiometry (DXA) or other validated tool for fracture risk prediction. Further details on screening and risk assessment are discussed elsewhere. (See 'Premenopausal women' above and 'Postmenopausal women' above and "Screening for osteoporosis in postmenopausal women and men", section on 'Fracture risk assessment'.)

●Osteoclast inhibitors for bone density loss and reducing the risk of fracture – For women found to have osteoporosis based upon a DXA scan (T score of -2.5 or lower or a history of fracture due to low BMD), or osteopenia with additional risk of fracture, we use an osteoclast inhibitor, similar to the approach adopted for those without a history of cancer. Additionally, we provide counseling on nutritional, exercise, and healthy lifestyle behavior. Further details on screening and risk assessment are discussed elsewhere. (See 'Premenopausal women' above and 'Postmenopausal women' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Evaluation and treatment of premenopausal osteoporosis".)

●Bisphosphonates for anticancer therapy – For postmenopausal women (naturally, surgically, or chemically induced) with a moderate to high risk of distant recurrence (10 percent or higher) receiving any form of adjuvant systemic therapy, we suggest adjuvant bisphosphonates (algorithm 1) (Grade 2C). However, the absolute benefits of adjuvant bisphosphonate therapy are likely to be small, and some patients and clinicians may opt not to consider this treatment given the potential for toxicity and concerns about modest efficacy. The NHS PREDICT tool online may inform the doctor-patient discussion on the potential benefit of adjuvant bisphosphonate therapy. (See 'Bisphosphonates for anticancer therapy' above.)

•While denosumab is an option for reducing the risk of osteoporosis and fracture, trials of adjuvant denosumab show conflicting results in regards to disease-free survival (DFS), and no trial has shown an uncensored statistically significant overall survival benefit. Therefore, based on available data, we do not utilize denosumab for indications other than bone health. (See 'Denosumab for anticancer therapy' above.)

●Choice of agent – In postmenopausal women receiving adjuvant bisphosphonates, we suggest zoledronic acid or clodronate (Grade 2C), and consider oral ibandronate a less favored alternative (as there are no direct data supporting a DFS benefit with this agent). Present international guidelines recommend use of zoledronic acid 4 mg intravenously every six months for three to five years, zoledronic acid 4 mg intravenously every three months for two years, clodronate 1600 mg orally daily for two to three years, or ibandronate 50 mg orally daily for three years.

The doses of zoledronic acid and ibandronate are not the standard osteoporosis dose, and are not approved by the US Food and Drug Administration (FDA). Clodronate (at any dose) is not approved by the FDA, but is available outside of the United States.

•Most studies started the bisphosphonate shortly after surgery or chemotherapy.

•The side effects of therapy may be serious and include a low risk of osteonecrosis of the jaw or atypical fracture of the jaw. Other side effects include gastrointestinal, renal, and electrolyte disturbances as well as acute phase reactions. (See 'Toxicity associated with osteoclast inhibitors' above.)