The majority of breast cancers are hormone receptor-positive and are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Women with hormone receptor-positive breast cancer are often treated with aromatase inhibitors (AIs), or other forms of endocrine (hormonal) therapy.
Historically, tamoxifen was the main anti-estrogen endocrine therapy used to treat breast cancer patients. More recently, AIs have demonstrated improved outcomes compared with tamoxifen among postmenopausal women. Researchers continue to assess side effects associated with AIs in order to reduce or prevent these complications altogether.
All endocrine therapy including AIs suppress estrogen levels which causes bone loss and can increase the risk of bone fractures. Use of drugs that reduce bone loss benefits women who are treated with endocrine therapy.
Bisphosphonate drugs can be used to reduce the risk of pathological fracture caused by metastatic bone lesions and for the treatment of bone pain. Bisphosphonate drugs work by inhibiting cells in the bone called osteoclasts, which resorb or break down bone tissue. This action effectively prevents the loss of bone that occurs from metastatic lesions.
There have been several studies evaluating bisphosphonates to reduce the risk of bone loss and fractures in women being treated with endocrine therapy
The Z-fast study
The Z-fast study assessed zoledronic acid, a potent IV bisphosphonate, given at a dose of 4mg every six months to postmenopausal patients receiving Femara (letrozole), a widely used AI.1 In the study women were either started on zoledronic acid right away or when their bone density fell, as evaluated by DEXA scan [means of measuring BMD]. The study showed a highly significant increase in bone mineral density for women treated with zoledronic acid immediately that continued to improve through 36 months of treatment with Femara. Conversely, women in the group who received delayed use of Femara had a reduction in BMD though 36 months indicating that use of zoledronic acid every six months preserved and actually improved bone mineral density for patients on AIs.
The Austrian Breast Cancer Trial Group also evaluated ovarian suppression in premenopausal women along with either tamoxifen or the AI anastrozole. As part of the study, some patients also received zoledronic acid. Among patients who did not receive zoledronic acid, there was a significant drop in bone mineral density in the lumbar spine for patients who received tamoxifen plus ovarian suppression or anastrozole plus ovarian suppression. Among patients who did receive zoledronic acid, bone mineral density was improved at five years in both the tamoxifen and anastrozole arms. The overall difference between zoledronic acid and no-zoledronic acid was 10% net improvement in bone density at five years.2
Can Bisphosphonates Treat Breast Cancer?
Adjuvant bisphosphonate treatment is reported to significantly improves breast cancer survival and reduce bone recurrences in postmenopausal women with early breast cancer, according to a large meta-analysis of 36 randomized controlled trials that included a total of 22,982 women. The studies compared the adjuvant use of bisphosphonate to no bisphosphonate or placebo.7
Researchers found that women taking bisphosphonates had a highly significant reduction in distant cancer recurrence—the rate of recurrence was 18% among postmenopausal women taking bisphosphonates compared to 22% in those not taking them. Bisphosphonates also appeared to reduce the rate of bone recurrence in postmenopausal women—the rate of bone recurrence among women taking bisphosphonates was 6% percent compared with 9% percent for the other women. There was no significant effect on non-bone recurrence.
Notably, the rate of breast cancer mortality was 15% among women taking bisphosphonates compared with 18% among their counterparts. The rate of all-cause mortality was 21% percent in the bisphosphonate group compared with 24% in the other group.
The researchers concluded that adjuvant use of bisphosphonates reduced the risk of bone recurrence by 34 percent and the risk of breast cancer death by 17 percent in postmenopausal women with early breast cancer. In addition, adjuvant bisphosphonates led to an absolute reduction of 3.4% in all-cause mortality.
Practical guidance for the prevention of AI-associated bone loss
A meta analyses of risk factors for bone loss that included not only AIs but other known factors that were both patient-specific and historical suggests that all patients on an AI should receive calcium and vitamin D supplements, and that patients with a baseline T-score [comparison of a patient’s BMD to that of a healthy thirty-year-old of the same sex and ethnicity] by DEXA scan of less than 2 should receive zoledronic acid 4 mg every 6 months IV. They also recommended zoledronic acid for AI-treated patients with any two of the following risk factors:
- T-score less than 1.5, consistent with osteopenia
- Age over 65
- Low BMI [body mass index]
- Family history of fracture
- Personal history of fragility fracture after age 50
- Oral corticosteroid use after 6 months
- Current smoking
They recommended that treatment should continue for at least two years, pending the long-term results of the Z-fast study and other studies that are looking at long-term usage of zoledronic acid in patients receiving AIs. I think these are useful recommendations and ones that we certainly need to incorporate into our routine practice so that we can preserve the benefit of AIs without the common potential side effects.
About Bisphosphonates
Bones are constantly remodeling in a process that removes old bone cells and deposits new ones. This process is accelerated when estrogen is reduced or blocked. Bisphosphonates are a group of medicines that slow down or prevent bone loss, strengthening bones. Bisphosphonates help prevent the bones from losing calcium and other minerals by slowing or stopping the natural processes that dissolve bone tissue. Bisphosphonates inhibit osteoclasts which are the cells responsible for breaking down and reabsorbing minerals such as calcium from bone (the process is known as bone resorption). Bisphosphonates allow osteoblasts (bone building cells) to work more effectively, improving bone mass.
Bisphosphonates
- Risedronate (Actonel)
- Alendronate (Fosamax)
- Ibandronate (Boniva)
- Zoledronic Acid (Reclast)
- Pamidronate (Aredia)
- Etidronate (Didronel)
Bisphosphonate Side Effects
The most common side effects of bisphosphonates are stomach irritation and heartburn, but these problems are often avoided by taking the medication correctly.
Other common side effects include:
- Bone or joint pain, or generalized pain
- Muscle cramps or aches
- Nausea, constipation diarrhea, or other stomach discomfort
- Headache or dizziness
- Bladder infections
- Tiredness or trouble sleeping
Can Bisphosphonates Reduce the Risk of Breast Cancer?
Two studies have provided additional evidence that use of bisphosphonates to treat osteoporosis may actually reduce the risk of invasive breast cancer in postmenopausal women. The results of these studies were published in the Journal of Clinical Oncology.
Two studies published in the same issue of the Journal of Clinical Oncology reported on the relationship between bisphosphonate use and risk of postmenopausal breast cancer. The first study evaluated information from more than 150,000 participants in the Women’s Health Initiative studies.4 The studies enrolled postmenopausal women between the ages of 50 and 70.
The focus of the analysis was oral bisphosphonate use. Of the more than 150,000 study participants, 2,816 were users of oral bisphosphonates at the time of study entry. The most commonly used oral bisphosphonate was Fosamax® (alendronate).
After an average of more than seven years of follow-up, risk of invasive breast cancer was 32% lower among bisphosphonate users. A reduced risk was observed for both estrogen receptor (ER)-positive as well as ER-negative cancers, although the result for ER-negative cancers did not meet the criteria for statistical significance (suggesting that it could have occurred by chance alone). Risk of ductal carcinoma in situ (DCIS) was higher in bisphosphonate users; the researchers note that the clinical significance of this finding is uncertain.
The second study involved the Breast Cancer in Northern Israel Study.5 The study collected information for 4,039 postmenopausal women with and without breast cancer.
The results indicated that use of bisphosphonates for more than one year reduced the risk of breast cancer by 39%. Breast cancers in bisphosphonate users were more likely to be ER-positive and less likely to be poorly differentiated.
These studies provide additional evidence that bisphosphonates may reduce the risk of invasive breast cancer. An accompanying editorial notes: “At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone protecting effects, when evaluating treatment options in women with postmenopausal osteoporosis, especially considering that bisphosphonates are generally well tolerated in this population.”6
Like most drugs, bisphosphonates carry a risk of side effects. Women who are considering bisphosphonate use to manage osteoporosis are advised to talk with their doctor about the risks and benefits.
References:
- Brufsky A, Bosserman L, Caradonna R et al. The effect of zoledronic acid on aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: the Z-FAST study 36 month follow-up. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 27.
- Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al. Bone mineral density (BMD) at 5 years after diagnosis in premenopausal patients with endocrine-responsive breast cancer, after 3 years of adjuvant endocrine treatment with goserelin and tamoxifen or anastrozole or both treatments in combination with zoledronic acid new results from ABCSG-12. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 26.
- Hadji P, Appro M, Brufsky A et al. Practical guidance for the prevention of aromatase inhibitor-associated bone loss in women with breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 504.
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Chlebowski RT, Chen Z, Cauley JA et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. Journal of Clinical Oncology [early online publication]. June 21, 2010.
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Gnant M. Can oral bisphosphonates really reduce the risk of breast cancer in healthy women? Journal of Clinical Oncology [early online publication]. June 21, 2010
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Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of postmenopausal breast cancer. Journal of Clinical Oncology [early online publication]. June 21, 2010.
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Coleman R, Gnant M, Paterson A, et al. Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S4-07.
