Guiding principles recommend that bisphosphonates be used as adjuvant therapy for women in post-menopause who are diagnosed with early-stage breast cancer.
Two years ago, at the age of 44, Susan Leonard was diagnosed with stage II breast cancer – a disease that affects over 260,000 American women on an annual basis. In order to keep her cancer from recurring, she had to undergo countless treatments, including chemotherapy, hormone therapy, a double mastectomy, and prophylactic ovary removal. The treatments put her into menopause, as well as at a severe risk for decreased bone health or rather, for osteoporosis.
To prevent the onset of this bone disease, Susan received an injection of Zometa, which is a medication that belongs to a group of medications known as bisphosphonates. The main objective of these medications is to prevent the loss of bone density and to treat osteoporosis and similar diseases. However, in Susan’s case, the hope was that the injection, given two times a year, would be beneficial to her health in another way - by stopping her cancer from spreading to her bones.
Evidence of effectiveness
In women diagnosed with breast cancer, bisphosphonates are generally prescribed to prevent and treat osteoporosis related to consequences following cancer treatment.
Nevertheless, researchers remain puzzled as to how bisphosphonates stop breast cancer from attacking the bones in the first place. It is believed that cancerous cells of the bones stimulate cells known as osteoclasts, which are responsible for causing fragile bones. And bisphosphonates work by inhibiting this process, all the while facilitating in the production of bone-building cells known as osteoblasts.
What researchers are clear on is that clinical trials conducted in the past and the ones currently underway continue to indicate the effectiveness of bisphosphonates in modifying the onset of bone disease following breast cancer surgery and other systemic therapies. Consistent with a meta-analysis conducted back in 2015, it was found that bisphosphonates could stop cancer from spreading to the bones in women of post-menopausal status. More specifically, 26 randomized controlled trials followed a total of 18,766 women diagnosed with early-stage breast cancer and revealed a 10-year risk reduction (in comparison to a control group) by:
- 1.1 % - bone recurrence;
- 1.7% - breast cancer mortality;
- 1.4% - distance recurrence;
In these women, no significant changes were found in breast cancer recurrence and all-cause mortality. However, in 11,767 of the women who were in post-menopause, the 10-year risk reduction (in comparison to a control group) was seen by:
- 2.2% - bone recurrence;
- 3.3% - breast cancer mortality;
- 3.4% - distance recurrence;
- 3% - breast cancer recurrence;
- 2.3% - all-cause mortality.
As a result, the benefits of bisphosphonates were seen solely among the women who were in post-menopause.
Measuring side effects
Guiding principles recommend that bisphosphonates be used as adjuvant therapy for women in post-menopause who are diagnosed with early-stage breast cancer. Two options are considered to be viable: Zometa (given every 6 months for 3-5 years) and Bonefos (given daily for 2-3 years). Although these specific medications have proven to be associated with breast cancer benefits, their optimal dose and administration have yet to be determined.
In regards to safety and tolerability, use of bisphosphonates often triggers severe side effects, including bone and joint pain, and flu-like symptoms. However, symptoms tend to improve within a few days or following the initial few injections.
Although rare, other severe side effects resulting from the use of bisphosphonates include osteonecrosis of the jaw and gradual loss of kidney function. In Susan’s case, for a month and a half before and for a month and a half following her injections, her doctor advised her to avoid any dental work that could put her at a greater risk for osteonecrosis of the jaw. Additionally, her breast cancer treatments resulted in her becoming affected by arthritis, why is why it was rather difficult to tell if the Zometa triggered any additional bone pain. “I had terrible bloating for four days but otherwise I felt okay” she said. Regardless, Susan stressed that taking Zometa has given her a sense of tranquility and with time, she hopes that the injections will pay off.
Strengths and limitations
A meta-analysis conducted back in 2017 followed over 175,000 women diagnosed with breast cancer from all around the globe. Out of the women diagnosed with early-stage breast cancer (stage I, II and III), 12% developed bone disease within the first 5 years after initial diagnosis. Out of the women whose disease had spread to other organs in their body, 55% were also affected by bone disease.
Once breast cancer has had a chance to spread beyond the breast and lymph nodes, it reaches an advanced stage, also known as stage IV. This stage is considered fatal, with a majority of women having a life expectancy average of 3 years. “When breast cancer metastasizes…the most common distant organ is bone. In autopsy analysis, approximately 70% of people who have died from breast cancer have bone metastasis. So, the idea of having something that may impact recurrence to the bone is going to be of interest” said Catherine Hall Van Poznak, associate professor at the University of Michigan Medical Center.
Clinical trials conducted to date support the use of bisphosphonates as adjuvant therapy. Findings reveal that these medications may be able to help hinder breast cancer recurrence and to improve survival rates among women diagnosed with the disease at an early stage. However, it remains unclear whether differences in standard breast cancer management of women in pre and postmenopause participating in these trials may be responsible for the differences in benefits to these population groups. Moreover, it remains unclear whether chemotherapy was used for breast cancer treatment, as well as whether it reflected current clinical practice guidelines for treatment across all of the trials.
As a woman progresses from premenopause to postmenopause, the complex relationships between reproductive hormones, bone cell function, and tumor biology could change as well. For now, it comes down to weighing the worth of bisphosphonates as adjuvant therapy based on the response of each individual patient.
Further research is necessary in order to accurately determine whether women diagnosed with breast cancer who develop osteoporosis during treatment are at an increased risk for developing bone disease. Nevertheless, given the common occurrence of breast cancer-related bone disease, this issue remains a concern.