As survival is improving for women with metastatic breast cancer (MBC), managing bone health requires a more nuanced approach. This article explores how to balance the benefits of bone-directed therapies with long-term risks, with a focus on toxicity, oral health, and supportive care strategies.

Most women with MBC will develop bone metastases over the course of their disease, especially those with HR+ disease. For them, the adjunctive use of intravenous bisphosphonates or the RANKL inhibitor denosumab decreases skeletal-related complications, including spinal cord compression and hypercalcemia, and reduces the need for palliative radiation or orthopedic stabilization. While we are treating bone metastases, we are also improving overall bone health.

Since the initial US Food and Drug Administration (FDA) approval of adjunctive bone-directed therapies for MBC, a number of new treatments have also been approved that have prolonged the life expectancy of women with advanced breast cancer. In the age of combination therapy with CDK4/6 and PI3K inhibitors, patients with HR+/HER2- MBC are living longer and have more prolonged exposure to monthly or every 3- to 6-month administration of antiresorptive therapy. This has resulted in an increase in unusual toxicities such as atypical femoral fractures and osteonecrosis of the jaw (ONJ).

A recent study looked at the incidence of medication-related ONJ (MRONJ) in 639 patients with MBC who received monthly antiresorptive therapy. The median time for developing MRONJ was 4.6 years for patients treated with denosumab, 5.1 years for those treated with bisphosphonates, and 8.4 years for those treated with both denosumab and bisphosphonates consecutively. Additionally, the cumulative incidence of MRONJ was 11.6% with denosumab and 2.8% with bisphosphonates; patients who transitioned from a bisphosphonate to denosumab experienced an incidence of 16.3%. This is an important study because it highlights the potential complication of prolonged bone-directed therapy, which is likely attributed to the fact that women with MBC are living longer. ONJ is a devastating complication that is associated with an increased risk of dental abscess and discomfort.

Atypical femoral fractures have been reported with the prolonged treatment of osteoporosis with bisphosphonates, and they have also been reported in women with MBC treated with prolonged intravenous bisphosphonate therapy. In the MBC setting, in which patients receive bone-directed therapy, we do not generally perform a dual-energy x-ray absorptiometry (DEXA) scan because it is not going to influence treatment decisions. In the absence of clinical trials that inform the ideal duration of these therapies, we must rely on clinical judgment. The assessment of bone health using DEXA is important for all postmenopausal women, including those who became postmenopausal as a result of treatment. Postmenopausal women will typically get a DEXA scan prior to receiving adjuvant bisphosphonates and at 2-year intervals thereafter.

All women, especially those with bone loss, are encouraged to take vitamin D, ingest adequate amounts of calcium, and participate in strength and aerobic exercise. Ideally, calcium should come from food, as some data have linked supplemental calcium to an increased risk of coronary artery disease. Exercise is not only important for bone density but it also helps with balance and strength, making falls less likely. And, while any exercise is helpful, exercise with impact (ie, resistance training) is most helpful at improving bone density.

As women with MBC are living longer, it is important that we recognize the long-term complications associated with aging and cancer treatment. It is important to monitor patients’ oral health carefully, especially in those receiving monthly denosumab. Finally, it is equally important that we address bone health in our long-term survivors who may be at risk for bone loss.