Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer

Publication Date: January 18, 2022
Last Updated: July 6, 2022

Key Points

Key Points

  • In 2017 an American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario) meta-analysis noted significant benefit from bisphosphonates in all postmenopausal breast cancer patients for bone recurrence (6.6% vs. 8.8%), fracture rates (9.1% vs. 10.3%), breast cancer mortality (14.7% vs. 18.0%), overall survival (OS) (any death 21.1% vs. 23.5%), and outcomes that included bone recurrence (i.e., distant recurrence, any recurrence) and made treatment recommendations based on those findings.
  • This update concerns the choice and dose of bisphosphonates, the use of denosumab and a revision of patient selection based on three recently published studies.



Table 1. Complete List of Recommendationsa

New Recommendations from 2021 ASCO-OH Focused Guideline Update

Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and Human Epidermal Growth Factor Receptor 2 (HER2) status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. ( IC , , I , M )
The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool ( provides estimates of benefit of adjuvant bisphosphonate therapy and may aid in shared decision-making.

Factors influencing the decision to recommend adjuvant bisphosphonate use that should be weighed in the discussion with patients include the patient’s risk of recurrence, the risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy.
The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline. Many studies initiated bisphosphonate within 3 months of definitive surgery or within 2 months of completion of adjuvant chemotherapy; this is a consensus recommendation. The therapeutic options, listed alphabetically, with the strongest supporting data include:
  • oral clodronate (1,600 mg daily for 2 to 3 years)
  • oral ibandronate (50 mg daily for 3 years)
  • zoledronic acid; dosing regimens as per the protocols of the clinical trials (including the option of 4 mg every 6 months for 3 years or 4 mg every 3 months for 2 years)

Patient preference should be factored into the choice of adjuvant bisphosphonate therapy. Access to adjuvant bisphosphonate therapy may currently limit choice of agent depending on jurisdiction. ( EB , , I , M )
The Panel does not recommend the use of adjuvant denosumab. ( EB , B , I , M )
Key evidence:
Two Phase III studies of adjuvant denosumab did not show a consistent reduction of breast cancer recurrence in any subset of patients with early-stage breast cancer. The larger study, D-CARE, did not show improvement in cancer outcomes with use of denosumab.

Recommendations Unchanged From 2017 CCO-ASCO Guideline

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 people age ≤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. (, , , )
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 (ONJ), especially with tooth extractions and other invasive dental procedures. Patients should inform their dental practitioner of their treatment.
Patients with suspected ONJ 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 intravenous 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.
From the 2017 CCO -ASCO Guideline and the ASCO -OH (CCO) 2021 Focused Guideline Update.

Recommendation Grading


  • ASCO: American Society Of Clinical Oncology
  • CCO: Cancer Care Ontario
  • HER2: Human Epidermal Growth Factor Receptor 2
  • OH: Ontario Health
  • ONJ: Osteonecrosis Of The Jaw
  • OS: Overall Survival

Source Citation

Eisen A, Somerfield MR, Accordino MK, et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update. J Clin Oncol. 2021 Jan 18. doi:10.1200/JCO.21.02647


This pocket guide is derived from recommendations in the American Society of Clinical Oncology Guideline. This resource is a practice tool based on ASCO® practice guidelines and is not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients. This pocket guide does not purport to suggest any particular course of medical treatment. Use of the practice guidelines and this resource are voluntary. The practice guidelines and additional information are available at Copyright © 2021 by American Society of Clinical Oncology. All rights reserved.