An updated position statement on the management of aromatase inhibitor-associated bone loss (AIBL) in women with hormone-sensitive breast cancer provides the latest evidence-based guidance, with an emphasis on the clear benefits of bisphosphonates, not only in preventing the bone loss but also in providing potential anticancer effects.

“Women with breast cancer need to be aware that while treatment with aromatase inhibitors gives them better outcomes overall, there is a caveat of developing osteoporosis and fractures from the treatment — but these can be prevented with the use of bisphosphonates,” lead author Peyman Hadji, MD, of the Frankfurt Centre for Bone Health and Endocrinology, Frankfurt, and Philipps University of Marburg, Marburg, Germany, told Medscape Medical News.

Furthermore, “the use of bisphosphonates is associated with a 34% reduction in the risk of developing bone metastasis, which is by far the most prevalent metastasis in breast cancer,” he said.

Aromatase Inhibitors: A Breast Cancer Treatment Cornerstone With a Caveat

Aromatase inhibitors, a cornerstone in the adjuvant treatment of the approximately 80% of patients with breast cancer who have estrogen receptor (ER)-positive breast cancer, show significantly improved effects on cancer recurrence and other outcomes compared with the previous standard treatment, tamoxifen.

However, as opposed to tamoxifen, which shows no negative impact on bone mineral density (BMD) or fracture risk in postmenopausal women, aromatase inhibitors are associated with a twofold to fourfold increased risk for bone loss in postmenopausal women, posing the risk for osteoporosis and fragility fractures, due to the drugs’ reduction of estrogen levels.

Importantly, those effects can be offset by osteoporosis drugs including bisphosphonates as well as the antiresorptive drug denosumab.

The updated position statement, which addresses current evidence on the use of bisphosphonates and an array of other issues in the management of AIBL, was issued by an interdisciplinary group of cancer and bone societies, including the International Osteoporosis Foundation; Cancer and Bone Society; European Calcified Tissue Society; International Expert Group for AIBL; European Society for Clinical and Economics Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases; International Menopause Society; and International Society of Geriatric Oncology.

For the update, the groups conducted a systematic literature review of the latest evidence emerging since the previous statement, issued in 2017.

Bisphosphonate Evidence Upgraded to Level I

Among updates is that the evidence regarding bisphosphonates has become strong enough to upgrade the recommendation of intravenous bisphosphonates from level II evidence to level l in the prevention of the AIBL.

Key evidence driving the change came from the phase 3 AZURE trial, representing the largest study on fracture incidence with bisphosphonate use in breast cancer.

That study showed that the addition of the bisphosphonate zoledronic acid 4 mg for 5 years to standard neoadjuvant chemotherapy and/or endocrine therapy reduced the incidence of fractures in postmenopausal patients with stage II or II early breast cancer, with a 5-year fracture rate of 3.8% vs 5.9% in a control arm.

The study also showed that zoledronate significantly extended the time to first fracture (hazard ratio [HR], 0.69; P = .0053), with the majority of the fracture prevention benefit occurring following disease recurrence (HR, 0.30; P < .001).

Of note, only a small benefit on fracture risk was observed among women who had a sustained remission of their underlying cancer.

While oral bisphosphonates, designated as level III-IV evidence in the 2017 joint position statement were upgraded to level II in the new statement, the authors note that, in addition to adherence and gastrointestinal adverse effect concerns, the data largely come from small studies.

Anticancer Benefits

Importantly, as discussed in the 2017 guidelines, intravenous bisphosphonates in early breast cancer also show reductions in disease recurrence and breast cancer deaths in postmenopausal women, with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality, above and beyond their bone health benefits.

However, denosumab does not show similar anticancer benefits, and therefore “cannot be recommended for the prevention of disease recurrence in postmenopausal women with breast cancer,” the statement notes.

Additional considerations include that, compared with denosumab, bisphosphonates are relatively inexpensive and do not have the rebound effect associated with denosumab discontinuation.

“The question arises of why to use drug that only provides osteoporosis prevention but no cancer prevention when there is another drug providing both at once?” Hadji said.

Updated Treatment Algorithm

The consensus statement also includes some important updates to recommendations regarding bone density and microarchitecture assessment, based on data from a variety of studies.

Ultimately, “all women receiving aromatase inhibitor treatment should be informed of this significantly increased risk [to bone health] and its consequences and have their individual fracture risk evaluated to determine an appropriate management strategy,” the statement concludes.

“Regardless of fracture risk, preventative measures such as exercise and optimal calcium and vitamin D intake need to be ensured. If an increased fracture risk has been identified, suitable medical intervention should be proposed.”

The statement features an updated desktop algorithm for the management of bone health in women receiving aromatase inhibitor therapy.

The algorithm states that for patients with bone T scores > -2.0 and no additional risk factors, management can include recommendations of exercise, along with calcium and vitamin D and monitoring of risk and BMD at 1- to 2-year intervals.

For those with T scores < -2.0 and no additional risk factors, bisphosphonates or a sequence of denosumab-bisphosphonate therapy are recommended, along with exercise and calcium or vitamin D, with BMD monitoring every 2 years, in addition to regularly checking for adherence to bone-preserving therapies.

The recommendations for those with T scores < -2.0 also apply to patients who have any two of these risk factors:

• Age 65 years or older
• T score < -1.5
• Current or history of smoking
• BMI < 24
• Family history of hip fracture
• Personal history of fragility fracture above 50 years of age
• Vertebral fracture
• Oral glucocorticoid use for more than 6 months

Recent real-world research demonstrates that even prior to the new updates, the 2017 guidelines had a significant impact on the prevention of fractures compared with earlier guidelines published by the National Osteoporosis Society UK in 2008, with a reduction in fractures from 12.5% prior to the 2017 guidelines to 2.5% post-2017.

“This was an absolute risk reduction of 10%, which has implications for healthcare systems worldwide, [indicating that] this approach can reduce morbidity,” senior author Muhammad K. Nisar, MD, of Luton & Dunstable University Hospital, Luton, England, told Medscape Medical News.

He noted that “the new guidelines include a broader group of women — both pre- and postmenopausal — with advice on differential benefits of two main classes of antiresorptive, with a focus on sequencing of therapy.”

“This will help treat even more at-risk women and hopefully improve fracture-free cancer survival,” said Nisar.

Challenges

Key ongoing issues that will require further clarification include the longer-term use and optimal duration of bone protective therapy now that aromatase inhibitor therapy use is recommended for up to 10 years, Nisar noted.

Furthermore, despite its lack of benefit in cancer recurrence, denosumab nevertheless remains important in high-risk postmenopausal women, with greater efficacy than bisphosphonates for fracture prevention even with normal BMD, he said.

“This poses a challenge if a woman [on aromatase inhibitors] is prescribed adjuvant bisphosphonate and DEXA (bone scan) dictates the need for more potent therapy such as denosumab,” he said. “This needs further research.”

Importantly, the updated guidance underscores personalized strategies for patients in tackling such individualized challenges.

“The guidance encourages oncologists and osteoporosis specialists to work together to create a personalized, evidence-based strategy that balances cancer care and bone health,” Nisar said.

Among the potential strategies recommended can be the careful sequencing of treatment, he noted.

“Combining sequential treatment with bisphosphonates after denosumab might help mitigate bone turnover rebound,” he said. “This is very topical and helps clinicians navigate a complex issue.”

Hadji and Nisar reported having no disclosures.