Is there a role for adjuvant bisphosphonates alongside standard adjuvant systemic therapy?


On the basis of current insights, there is no role yet for adjuvant bisphosphonates alongside standard adjuvant systemic therapy. If bisphosphonates are indicated for progressively increasing osteopaenia resulting in osteoporosis, these agents may have an additional favourable effect on the risk of recurrence.



Level 2

There are indications that zoledronic acid added to standard adjuvant systemic therapy in a hypo-oestrogenic setting may reduce the chance of recurrence.


A2        Gnant 2009

B          Eidtmann 2010, Coleman 2010

Literature summary

Adjuvant therapy with bisphosphonates

Two of the three published studies concerning adjuvant clodronate for breast cancer showed a survival advantage [Diel, 2008; Powles, 2006]. One study showed no difference [Saarto, 2004]. Two studies [Gnant, 2009; Eidtmann, 2010], described a disease-free survival advantage for the addition of zoledronate to standard adjuvant hormonal therapy. The Austrian breast cancer study group randomised 1,800 premenopausal women with hormone-receptor positive stage I-II breast cancer between 3 years of tamoxifen or 3 years of anastrozole, in combination with goserelin in both groups, and between receiving or not receiving zoledronic acid 4 mg i.v. 1x6 months for 3 years (2x2 factorial design). Only 5.4% of patients had received (neo)adjuvant chemotherapy. Eighty-five percent of patients had a strong hormonal therapy-sensitive tumour. There was no difference in recurrence-free survival between tamoxifen or anastrozole, but there was a 35% reduction in the chance of recurrence for the group that had received zoledronic acid (HR 0.65; 95%CI 0.46-0.92). It was also notable that aside from bone metastases, the group that had received zoledronic acid also had significantly less visceral metastases [Gnant, 2009]. Comparable results were reported for stage I-IIIa postmenopausal, ER+ and/or PgR+ breast cancer patients, who had received adjuvant letrozole for 5 years and in addition were randomised between an immediate start with zoledronic acid 4 mg i.v. 1x6 months or not until a fracture occurred or patients were at an increased risk of fracture [Eidtmann, 2010]. After a median follow-up of 36 months, an immediate start with zoledronic acid was found to give a 41% risk reduction in recurrence (HR 0.59; 95%CI 0.36-0.96; log-rank p=0.031) [Eidtmann, 2010]. The data of the AZURE study was presented during an as yet unpublished presentation at the San Antonio breast cancer symposium [Coleman, 2010]. This study randomised 3,360 patients with stage II-III breast cancer between receiving and not receiving zoledronate (6x4 mg i.v. q 3 or 4 weeks, 8x4 mg i.v. q 3 months, and 5x4 mg i.v. q 6 months) as an addition to standard adjuvant systemic therapy for a duration of 5 years. Of these patients, only 31% were more than 5 year postmenopausal, 78% were ER+, 32% had a T1 tumour, and 95% had undergone adjuvant chemotherapy. With a median follow-up of almost 5 years, there was no difference in disease-free survival (multivariate HR 0.98; 95%CI 0.85-1.13; p=0.79). ER status was not found to play a role in analyses of subgroups defined beforehand, but menopausal status was. In women who were more than 5 years postmenopausal, addition of zoledronate provided an improvement in survival (multivariate HR 0.71; 95%CI 0.54-0.94; p=0.017). This group showed a reduction in locoregional recurrences, as well as in bone metastases and visceral metastases. There was no added value for zoledronate in the other group. Coleman (2010) concluded that adjuvant bisphosphonates only work in an oestrogen-poor environment.



In one-third of patients treated with a bisphosphonate, an acute phase reaction develops after the first administration of i.v. of the monthly oral dose, including fever, muscle ache, and lymphopaenia [Watts, 2010]. Osteonecrosis of the jaw is a relatively rare, but serious complication in which jaw bone becomes exposed and does not heal within 8 weeks [Khosla, 2007]. Bisphosphonate therapy for osteoporosis rarely leads to this disorder (1 in 10,000 to <1 in 100,000 patient years), but the risk is much higher in cancer patients (1-10 per 100 patients) [Khosla, 2007]. Particular risk factors are treatment with zoledronate, pamidronate followed by zoledronate, higher cumulative doses of bisphosphonates, poor oral hygiene and interventions of the jaw bone [Hoff, 2008]. It is important to inform patients of possible side effects prior to starting treatment and to ensure any interventions of the jaw are carried out first. In case of unavoidable interventions during bisphosphonate therapy, it is recommended that prophylactic antibiotics are administered prior to the intervention [Woo, 2006]. Osteonecrosis of the jaw appears to be a rare side effect of oral bisphosphonates [Woo, 2006]. Bisphosphonates may be administered if there is a clearance of at least 30 ml/min. Renal function disorders are related to the peak dose and rarely occur with correct intravenous administration [Watts, 2010].


Preclinical and partly also clinical research suggests that bisphosphonates inhibit tumour cell proliferation, inhibit angiogenesis and stimulate yδ T cell antitumour activity. In addition, they inhibit tumour cell adhesion to bone and extracellular matrix [Clezardin, 2005]. However, trial results are not univocal and the beneficial effect of these agents is probably limited to a particular subgroup of patients that cannot be clearly defined yet. Use of these agents as adjuvant therapy has therefore not yet become standard.

Authorization date and validity

Last review : 13-02-2012

Last authorization : 13-02-2012

The national Breast Cancer guideline 2012 is a living guideline, in other words there is no standard term of revision. NABON continually watches at new developments and clinical problems in the areas of screening, diagnostics, treatment and aftercare, and whether this requires an update.

Initiative and authorization

Initiative : Nationaal Borstkanker Overleg Nederland

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Psychiatrie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Approximately 14,000 women (and 100 men) are diagnosed with invasive breast cancer each year in the Netherlands, and about 1,900 have an in situ carcinoma. A woman's risk of having breast cancer over the course of her life is 12-13%. This means that breast cancer is the most common form of cancer in women in the Netherlands. Early detection, particularly via national breast cancer screening, combined with adjuvant therapy followed by locoregional treatment, improves the prognosis in women with breast cancer

The guideline on Breast Cancer Screening and Diagnostics, published in 2000, was updated in 2007. In 2002, the first multidisciplinary National Breast Cancer Guideline was published, it was revised in 2004, 2005 and 2006. In 2008 both guidelines were combined to Breast Cancer Guideline, which 2012 revision is now effected.

Scope and target group

This guideline is written for all the members of the professional groups that have contributed to its development.


This guideline is a document with recommendations and instructions to support daily practice. The guideline is based on the results of scientific research and expert opinion, with the aim of establishing good medical practice. It specifies the best general care for women with (suspected) breast cancer and for those who are eligible for screening. The guideline aims to serve as a guide for the daily practice of breast cancer screening, diagnostics, treatment and aftercare. This guideline is also used in the creation of informational materials for patients, in cooperation with the KWF (Dutch Cancer Society).

Samenstelling werkgroep

A core group consisting of a radiologist, surgeon, pathologist, medical oncologist and radiation therapist began preparing for the revision of the breast cancer practice guidelines in 2009. A multidisciplinary guideline development group was formed in early 2010 to implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society) (see list of guideline development group members). The benefits of such a multidisciplinary approach are obvious: not only does it best reflect the care, but it offers the greatest possible expertise for the guideline. In composing the development group, geographic distribution of the members, balanced representation of the various organisations and agencies concerned, and a fair distribution in academic background were taken into account as much as possible.


The guideline development group received procedural and administrative support from IKNL (Comprehensive Cancer Centre for the Netherlands) and support on methodology from Bureau ME-TA. Partial funding was obtained from SKMS (Quality Funds Foundation of Dutch Medical Specialists). This subsidy would not have been possible without the extensive assistance provided by the NVvR (Radiological Society of the Netherlands).

Declaration of interest

Partial funding for the guideline revision was obtained from the Society of Dutch Medical Specialists in the framework of the SKMS. IKNL sponsored some of the cost. On two occasions, as well as at the beginning and end of the process, all of the members of the guideline development group were asked to fill out a statement of potential conflicts of interest, in which they stated their relationship with the pharmaceutical industry. A list of these statements of interest can be found in the appendices.

Patient involvement

In developing this guideline, four clinical questions were formulated. These questions emerge from an inventory of clinical problems collected in the field from professionals, patients and patient representatives.


Also, A multidisciplinary guideline development group was formed in early 2010 to create and implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society).


Method of development

Evidence based


Feasibility has been taken into account in developing the guideline. This included attention to factors that could promote or hinder putting the advice into practice. Examples include the implementation of an analysis of problems, the multidisciplinary composition of the guideline development group, and making active use of support from the guideline development group members. Presenting the draft guideline to the field and communicating what, if anything, is being done with the responses, also promotes implementation. In this manner, a guideline has been developed that answers current questions in the field.

The guideline is distributed widely and is available in digital form on the Dutch Guideline Database. The guideline may also be brought to the attention of a wider audience in other periodicals or continuing education sessions, for example. To promote use of the guideline, we recommend that the regional tumour working groups and group practices, as well as scientific and professional organisations, repeatedly bring the guideline to the attention of their members. Any problems that may arise in using the guidelines can then be discussed and, when appropriate, submitted to the national guideline development group, as it is a "living" guideline. If desirable, parts of the guideline can be made more explicit by formulating regional additions or translation to the local situation in departmental and/or hospital protocols.

In principle, indicators are determined during development of the guideline that can be used to monitor implementation of the recommendations. Via a documentation project, these indicators can then be used to determine the extent of compliance with the guideline. The information from the documentation project becomes input for the revision of the guideline.

Methods and proces

This module has been evidence-based revised in 2008 and consensus based updated in 2012.


A revision of an existing guideline consists of revised and updated text. Revised text is new text based on an evidence-based review of the medical literature; updated text is the old guideline text which has been edited by the experts without performing a review of medical literature. Each section of the guideline states what type of revision has taken place. Each chapter of the guideline is structured according to a set format, given below. The purpose of this is to make the guideline transparent, so that each user can see on what literature and considerations the recommendations are based on.


Description of the literature

To the greatest extent possible, the answers to the fundamental questions (and therefore the recommendations in this guideline) were based on published scientific research. The articles selected were evaluated by an expert in methodology for their research quality, and graded in proportion to evidence using the following classification system:


Classification of research results based on level of evidence


Research   on the effects of diagnostics on clinical outcomes in a prospectively   monitored, well-defined patient group, with a predefined policy based on the   test outcomes to be investigated, or decision analysis research into the   effects of diagnostics on clinical outcomes based on results of a study of   A2-level and sufficient consideration is given to the interdependency of   diagnostic tests.


Research   relative to a reference test, where criteria for the test to be investigated   and for a reference test are predefined, with a good description of the test   and the clinical population to be investigated; this must involve a large   enough series of consecutive patients; predefined upper limits must be used,   and the results of the test and the "gold standard" must be   assessed independently. Interdependence is normally a feature of situations   involving multiple diagnostic tests, and their analysis must be adjusted   accordingly, for example using logistic regression.


Comparison   with a reference test, description of the test and population researched, but   without the other features mentioned in level A.


Non-comparative   trials


Opinions   of experts, such as guideline development group members



Based on the medical literature, one or more relevant conclusions are made for each section. The most important literature is listed according to the level of evidential strength, allowing conclusions to be drawn based on the level of
evidence. All the medical literature included in the conclusion is described in the bibliography.


Classification of conclusions based on literature analysis


Based   on 1 systematic review (A1) or at least 2 independent A2 reviews.


Based   on at least 2 independent B reviews


Based   on 1 level A2 of B research, or any level C research


Opinions   of experts, such as guideline development group members


Other considerations

Based on the conclusion(s), recommendations are made. However, there are other considerations that contribute to formulation of the recommendation besides literature evidence, such as safety, the patients' preferences, professional expertise, cost-effectiveness, organisational aspects and social consequences. The other considerations are mentioned separately. In this manner, it is clear how the guideline development group arrived at a particular recommendation.



The final wording of the recommendation is the result of the scientific conclusion, taking into account the other considerations. The purpose of following this procedure and drawing up the guidelines  in this format is to increase transparency.



An alphabetical list of literature references can be found at the end of the guideline.


All draft texts have been discussed by the guideline development group.

Search strategy

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