Bisphosphonates, long used to strengthen bones, may prevent recurrence of early-stage breast cancer in postmenopausal women.
In a way, developing low bone-mineral density may have been a lucky break for Beth Rothman.
She had been cancer-free for about two years when X-rays showed that her ongoing treatment with Femara (letrozole), which suppresses the hormone estrogen, was preventing her body from making new bone as quickly as it was reabsorbing old bone.
Her doctor diagnosed osteopenia, or low bone-mineral density, which can lead to fractures. The doctor recommended six infusions of Zometa (zoledronic acid), a widely used medication in a class of drugs called bisphosphonates, which prevent bone loss by killing the cells that break down and reabsorb old bone.
“It was a mild case of osteopenia, and part of me was reluctant to take yet another medication just to treat it, but I got on board when my doctor added there was new research suggesting that this bone-strengthening medication might also help keep my cancer from coming back,” says Rothman, now 59, who was diagnosed with stage 1 cancer in her right breast 10 years ago.
“There’s obviously no way to know whether the Zometa has helped keep me cancer-free these past eight years, but, if it has, then I was lucky to get osteopenia, because I’d have never received the Zometa without it,” she says.
Women like Rothman, who have taken bisphosphonates for osteopenia or osteoporosis, have long been just about the only beneficiaries of the drugs’ apparent — and recently recognized — ability to reduce breast cancer recurrence.
However, if leading researchers and learned societies have their way, bisphosphonates will soon be at least considered as a means of preventing recurrence in the majority of postmenopausal women who undergo surgery to remove early-stage breast cancer.
Many trials looking at patients of all ages with early-stage breast cancer found no overall benefit in recurrence prevention when bisphosphonates were given, but did identify benefit in a specific subset. Among postmenopausal women whose early-stage breast cancer disappears entirely after initial treatment, the use of either oral bisphosphonates, such as Bonefos (clodronate), or infusions, such as Zometa, reduces relative risk of recurrence in the bones by nearly 30 percent, overall breast cancer recurrence by 14 percent, and 10-year breast cancer mortality from 18 percent to under 15 percent.
“In the world of cancer drugs, those are massive numbers. If a newly developed medication produced them about equally in women with every different subtype of breast cancer, everyone would be dancing in the streets and happily paying $100,000 a year,” says Adam Brufsky, M.D., Ph.D., associate director of clinical investigation at the University of Pittsburgh Cancer Institute. “Instead, because bisphosphonates don’t have a corporate champion, and because we don’t really understand how they prevent recurrence, millions of women who should be using bisphosphonates aren’t using them. That will change eventually, I hope, because these drugs can prevent a very significant number of premature deaths.”
Many women may have avoided such deaths because they have used some form of bisphosphonate for osteopenia or osteoporosis, which afflicts a high percentage of patients with breast cancer. Their bone problems stem, in part, simply from age. Three-quarters of breast cancer survivors are 60 or older, and more than 20 percent of all postmenopausal American women have osteoporosis. Breast cancer increases the likelihood that postmenopausal patients will have weak bones, due to their treatment. The aromatase inhibitors Femara, Arimidex (anastrozole) and Aromasin (exemestane) are particularly associated with low bone density because they eliminate estrogen production.
Bisphosphonates have been a common treatment for such patients since the 1990s, and the drugs’ history goes back much further than that.
Indeed, bisphosphonates are anything but cutting-edge. They were developed in the 19th century as water softeners for use in agricultural irrigation. The observation that they bind to and shore up a mineral that coats human bones led Procter & Gamble to investigate potential medical and dental applications in the 1960s. Researchers first used the drugs to treat progressive bone disease in 1968.
Bisphosphonates are also anything but budget-busting. All drugs in the class are off patent and, according to Brufsky, retail for less than $1,000 a year — quite a bargain in an industry where some newer drugs cost more than $100,000 for a year’s worth of treatment.
Ironically, despite that monumental price differential, some health insurers are willing to finance these expensive treatments to fight cancer but deny claims from patients who want to use bisphosphonates for the very same reason.
Why? When drugs are patent-protected, their developers have an incentive to pay millions of dollars to petition the U.S. Food and Drug Administration (FDA) to approve the medications for new indications each time trials demonstrate that they have another use. Bisphosphonates were protected when they were approved to treat osteoporosis, but those patents expired before researchers convincingly demonstrated the drugs’ ability to prevent breast cancer recurrence. As a result, Brufsky says, with generic competition keeping prices and profits low, no company has a financial incentive to spend millions to get new indications for a drug like Bonefos or Zometa.
Formal FDA approval for a particular use is important, because many doctors are reluctant to advocate “off-label” drug uses, and many insurers are reluctant to cover them.
FDA approval is not the only factor that drives drug usage and coverage. Compelling research and treatment guidelines from learned societies also have influence, and some now support the wide use of bisphosphonates for the prevention of cancer recurrence.
A 2015 analysis that pooled results from 26 randomized trials that included 11,767 postmenopausal patients with early-stage breast cancer found that those who used any type of bisphosphonate for two to five years were less likely than non-users to experience bone recurrence (6.6 percent vs. 8.8 percent) or any recurrence (22.8 percent vs. 25.8 percent), or to die from cancer (14.7 percent vs. 18.0 percent) or from any cause (21.1 percent vs. 23.5 percent) in the decade that followed their initial diagnosis. No benefit was found in premenopausal women.
The results of that analysis and several newer trials convinced an expert panel from the American Society of Clinical Oncology to endorse Cancer Care Ontario guidelines recommending that oncologists at least consider giving bisphosphonates to a large portion of cancer-free patients.
“The first indications that these drugs prevented recurrence in at least some breast cancer patients came many years ago, but the trial results were never definitive.
Some trials would find benefit, and some wouldn’t, and no one really understood the inconsistency,” said Robert Coleman, M.D., lead author of the analysis and professor emeritus of medical oncology at the University of Sheffield.
“By pooling the patient numbers from so many trials, we could look at how bisphosphonate use affected different types of patients, and that solved the mystery,” Coleman says. “We found the drugs only improve outcomes in early-stage postmenopausal women who are cancer-free after initial treatment. They don’t help premenopausal women, or women with bone metastases, so the inclusion of such women in many trials obscured the benefits that bisphosphonates do provide to some patients.”
There is also some evidence that giving bisphosphonates with chemotherapy, before surgery, to postmenopausal women who have early-stage breast cancer is effective in treating the disease. A 2016 analysis of four randomized trials of this technique that included more than 1,200 such patients showed that adding Zometa nearly doubled, to 17.7 percent, the rate of pathological complete response in the breast. The rate in the breast and lymph nodes rose from 7.8 to 14.6 percent when Zometa was added to chemotherapy.
Another advantage: Bisphosphonates produce those benefits without causing long-term severe side effects in most patients. In fewer than one in 100 postmenopausal patients with breast cancer, bisphosphonates can cause painful, hard-to-treat damage to the jaw bone, as well as very rare fractures of the mid-femur. More typical side effects include severe flu-like symptoms, which tend to decrease with ongoing use.
“My first infusion made me feel worse than I ever felt with chemotherapy,” says Rothman, who lives in Princeton, New Jersey. “My joints ached. I felt feverish. It was horrible, but it was gone in 24 hours, and I never had any symptoms whatsoever from subsequent infusions.”
Some bisphosphonate users never develop side effects. Shirley Mertz, 71, got an infusion of Zometa every six weeks for nearly 11 years without suffering so much as a sniffle. Mertz, who lives in the suburbs of Chicago, began taking the medication in late 2003, 12 years after doctors had removed all traces of her early-stage cancer. The disease had finally recurred, starting in her spine and spreading throughout her skeleton and liver. Her doctor recommended Zometa because it was proven to reduce bone pain, slow the rate at which the metastases would damage bone and reduce the risk of fractures. She also thought it might help prevent the further spread of cancer through Mertz’s bones.
Subsequent research — most notably Coleman’s combined analysis — suggests that bisphosphonate usage does not slow cancer progression once bone metastases have formed, but other benefits are firmly established. That’s why bisphosphonates (or newer bone-strengthening drugs such as Xgeva [denosumab]) are formally approved and commonly used to treat the symptoms of bone metastases in all kinds of solid tumors.
Mertz was lucky. Although one oncologist gave her less than a year to live, the doctor she chose prescribed a more aggressive treatment that combined the targeted breast cancer treatment Herceptin (trastuzumab), an oral chemotherapy and Zometa. Just 10 months later, a positron emission tomography scan found no evidence of disease.
Official guidelines then and now called for continued bisphosphonate use to minimize any future bone damage. As a result, even though most trials follow patients for only two years, people outside of clinical trials who begin using the drugs for bone metastases tend to stay on them indefinitely, because they are never considered “cured,” even if all traces of the metastases disappear. Mertz, therefore, kept taking Zometa for bone health, and both she and her doctor hoped it would provide the further benefit of making her bones a less hospitable environment for new metastases.
It was unclear at the time whether bisphosphonates would discourage further recurrence in patients who showed no evidence of disease after a first recurrence. Even today, there isn’t enough evidence to answer many reasonable questions about how bisphosphonates should be used: Does any particular bisphosphonate work better for recurrence prevention than the others? Should doses designed to prevent recurrence be larger than, smaller than or about the same as doses designed to strengthen bones? Should the interval be every six months or every three months? Does a limited course of treatment provide ongoing benefit, or do patients need to keep taking the drugs? How, exactly, do bisphosphonates even prevent bone recurrences? Researchers have yet to find definitive answers. The sheer size of the benefits found by Coleman’s analysis has attracted research dollars from governments, academia and charities.
“We may never have all the answers we want, but there are trials going on right now that have been designed to answer some of our most important questions,” says Noopur S. Raje, M.D., a professor at Harvard Medical School, noting that bisphosphonates also prevent bone recurrence in her specialty, multiple myeloma. “Until then, all we can do is keep up to date with the research and the recommendations and try to do what makes sense.”
Few patients who develop bone metastases stay on bisphosphonates as long as Mertz did; the median survival time for patients with metastatic breast cancer is just three years. Indeed, when she passed the 10-year mark, her doctor began to worry about the impact of Zometa on her kidneys and suggested she switch to Xgeva.
She did, even though she knew that there is slim evidence that it prevents recurrence; the only study to find recurrence reduction with Xgeva is a relatively small one from Austria. Coleman is working on a study that should provide far more concrete evidence, but it won’t be out for more than a year.
“As a patient, I knew I was in uncharted territory, but I feel that bisphosphonate treatment kept me from having issues with my skeleton or bone pain, so I wanted to continue treatment,” Mertz says. “My doctor and I know the benefits and limitations of treatment, but I continue to show no evidence of disease on scans. That is huge for me. I can be active, live a full life, and pursue advocacy work. So, I’m going to stick with it.