Cancer Care Ontario and ASCO Clinical Practice Guideline: Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer

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As reported in the Journal of Clinical Oncology by Sukhbinder Dhesy-Thind, MD, MSc, FRCPC, of Juravinski Cancer Centre, Hamilton Health Sciences, and colleagues, Cancer Care Ontario and ASCO have issued a clinical practice guideline on the use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer.1

The two organizations convened a working group and expert panel to develop evidence-based recommendations based on a systematic review of the literature. Key points identified in the review included the following: adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with nonmetastatic breast cancer (including those with natural menopause or menopause induced by ovarian suppression or ablation); absolute benefit is greater in patients at higher risk of recurrence, and almost all trials were conducted in patients who also received systemic therapy; most studies evaluated zoledronic acid or clodronate, with data extremely limited for other bisphosphonates; and although denosumab (Xgeva) was found to reduce fractures, long-term survival data are still required.

Summary of Recommendations

Recommendations are summarized/reproduced here. In the guideline, each recommendation is accompanied by several qualifying statements (not included below) that, as stated by the panel, form an integral part of the recommendations.

Recommendation 1: It is recommended that administration of bisphosphonates as adjuvant therapy be considered for postmenopausal patients with breast cancer (including patients premenopausal before treatment who have menopause induced by ovarian suppression as detailed in Recommendation 5) deemed candidates for adjuvant systemic therapy.

The final decision of whether or not to administer bisphosphonates should be made during consultation between the patient and oncologist, taking into account patient and disease characteristics, including risk of recurrence, and weighing the potential benefits and risks (adverse effects).

Recommendation 2: Zoledronic acid and clodronate are the recommended bisphosphonates for adjuvant therapy in breast cancer.

There is a need for more information comparing different agents and schedules, and it is recommended that such trials be conducted to establish the utility and optimal administration of other bisphosphonates for adjuvant therapy.

Recommendation 3: Although results for adjuvant denosumab look promising, data are insufficient at this time to make any recommendation regarding its use in the adjuvant setting.

It is recommended that studies directly comparing denosumab with bisphosphonates and evaluating administration schedules be conducted.

Recommendation 4: For patients who will receive adjuvant bisphosphonates (Recommendation 1), zoledronic acid at 4 mg intravenously (IV) over 15 minutes (or longer) every 6 months for 3 to 5 years or clodronate orally at 1,600 mg/d for 2 to 3 years is recommended. Different durations may be considered.

More research is recommended comparing different bone-modifying agents, doses, dosing intervals, and durations.

Recommendation 5: For purposes of adjuvant bisphosphonate use, the definition of menopause should include both natural menopause (at least 12 months of amenorrhea prior to initiation of chemotherapy or endocrine therapy) and menopause induced by ovarian ablation or suppression (but not the cessation of menses due to chemotherapy alone). In women aged ≤ 60 years with a previous hysterectomy and ovaries left in place, luteinizing hormone, follicle-stimulating hormone, and serum estradiol should be in the postmenopausal range and measured prior to initiation of any systemic therapy to receive adjuvant bisphosphonates.

It is recommended that administration of bisphosphonates as adjuvant therapy be considered for postmenopausal patients with breast cancer deemed candidates for adjuvant systemic therapy.
— Sukhbinder Dhesy-Thind, MD, MSc, FRCPC

Recommendation 6: A dental assessment is recommended, where feasible, prior to commencement of bisphosphonates, and any pending dental or oral health problems should be dealt with prior to starting treatment, if possible. Patients should be informed of the risk of developing osteonecrosis of the jaw, especially with tooth extractions and other invasive dental procedures. Patients should inform their dental practitioner of their treatment. Patients with suspected osteonecrosis of the jaw should be referred to a dental practitioner with expertise in treating this condition. Recent guidelines or position papers by groups such as the International Task Force on Osteonecrosis of the Jaw, the American Association of Oral and Maxillofacial Surgeons, and the American Dental Association should be consulted.

Patients should have serum calcium measured prior to starting treatment. Patients receiving IV bisphosphonates (zoledronic acid) should be monitored for renal function prior to starting this treatment and for serum calcium and increase in serum creatinine throughout the treatment period.

Calcium and vitamin D supplementation is recommended unless otherwise contraindicated. Oral bisphosphonates and calcium should not be taken concurrently; several monographs suggest an interval of at least 2 hours to allow for maximum absorption.

Symptoms such as ocular pain or loss of vision may be due to serious inflammatory conditions such as uveitis or scleritis and should be promptly evaluated by an ophthalmologist. ■

DISCLOSURE: For full disclosures of the study authors, visit


1. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al: Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: A Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 35:2062-2081, 2017.

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