Risk vs. benefit: Bisphosphonates in breast cancer

These common drugs can curb metastasis to bone and may even keep DCIS in check, but side effects make education and awareness crucial
An X-ray image of the top of a person's skeleton -- part of their jaw, their neck, chest and shoulder.
Stock photo by Getty Images

Bisphosphonates are popular bone-targeting drugs. Older people take them to prevent and treat osteoporosis. Breast cancer patients, particularly those with metastatic disease, take them to prevent and treat bone lesions or “mets.” These bone agents are also given to people with lung, prostate, multiple myeloma and other cancers.

Proven to prevent fractures and keep metastatic bone disease at bay, these drugs might also have broader benefits. A new analysis by scientists at Fred Hutchinson Cancer Research Center in Seattle suggests the drugs might keep people diagnosed with DCIS — the very earliest form of breast cancer — from developing invasive disease.

But bisphosphonates and other bone-modifying agents, or BMAs, can also come with short- and long-term side effects. And that last includes heart disease, kidney toxicity and a rare but troubling condition known as osteonecrosis of the jaw, or ONJ, in which small portions of the jaw become exposed and don’t heal. Bizarrely, while bone drugs markedly reduce overall fractures, they can also, in rare cases, cause fractures.

What’s the story with BMAs in breast cancer? Do the benefits outweigh the risks? How prevalent are side effects like ONJ? Can you prevent it? What about cost? And access? We talked with patients, cancer researchers and clinicians to get their takes on bisphosphonates — and a chemical cousin, denosumab — and how these drugs currently fit into our oncology armamentarium.

Photo of Fred Hutch epidemiologist Dr. Christopher Li standing at a podium presenting data on a study.
Fred Hutch epidemiologist Dr. Christopher Li Fred Hutch file photo

A drug with many uses

Previous trials have shown bisphosphonates might help lower the risk of developing breast cancer in postmenopausal women and reduce recurrence and death in early stage breast cancer patients.   

New research out from epidemiologist Dr. Chris Li and others at the Hutch now suggests bisphosphonates may also keep women with ductal carcinoma in situ, or DCIS, from developing invasive disease.

“Twenty percent of all breast cancers (in the U.S.) are DCIS,” said Li, lead author of the study published last month in the journal Cancer Research. “DCIS has a very high survival rate, but women with a history of DCIS have an elevated risk of developing a subsequent invasive breast cancer. This study suggests that bisphosphonates may lower this risk.”

As this is the first study to report on this relationship, the results will need to be confirmed, Li said; it won’t change clinical practice any time soon.

But it does reflect a growing interest in expanding the use of these drugs into another cancer population. And raises important questions about the tradeoffs, the risks vs. benefits, which researchers continue to investigate.

Photograph of Dr. Poorni Manohar wearing a dark jacket and lovely pink and white scarf.

'With metastatic breast cancer, we are trying to preserve the patient's quality of life. If someone has just one site of disease, I might not strongly push (these bone agents). It’s a fine balance to achieve. Women with metastatic disease will be on this drug indefinitely.'

— Fred Hutch / SCCA / UW physician-scientist Dr. Poorni Manohar

Photograph of Dr. Julie Gralow speaking at a podium, with two Fred Hutch researchers in the background.
Clinical researcher and breast cancer oncologist Dr. Julie Gralow, newly named chief medical officer of the American Society for Clinical Oncology, called bone-modifying agents a "proven therapy" for breast cancer patients. Fred Hutch file photo

‘A proven therapy’

Breast cancer treatment — especially anti-estrogen therapy — is hard on the bones. It accelerates the aging process, throwing many patients into early menopause (either surgically or chemically) and that can trigger bone loss, osteoporosis and fractures. Cancer wreaks similar havoc. Metastatic bone disease can cause a cascade of collateral damage — from deep, difficult-to-treat pain to debilitating fractures and worse.

That’s where BMAs come in. Rigorously studied for decades, they’ve become a cornerstone of treatment in breast cancer, with their use recommended in both early and advanced breast cancer patients by the American Society of Clinical Oncology, or ASCO, and the National Cancer Comprehensive Network, which develops guidelines for cancer treatment.

“In breast cancer, drugs that block bone breakdown are a proven therapy when bone metastases are present, reducing fractures, pain and the requirement for surgery and radiation,” said Dr. Julie Gralow, new chief medical officer for ASCO. A former Hutch clinical researcher and head of breast oncology at Seattle Cancer Care Alliance, Gralow has studied BMAs extensively through the SWOG Cancer Research Network.

She recently investigated the efficacy and side effect profile of three BMAs (IV-infused zoledronic acid and two oral agents) in a Phase 3 randomized trial. All three agents effectively fended off bone mets, but the researchers saw a bit more osteonecrosis of the jaw with zoledronic acid.

“These drugs do have some side effects including kidney toxicity, a first-infusion flu-like effect and ONJ,” Gralow said. “But these risks are far lower than the benefits in the metastatic setting.”

‘A fine balance’

Dr. Poorni Manohar, a physician-researcher with the Hutch and SCCA, is selective about using the drugs. In the early-stage setting, she said she’d recommend it to someone whose DEXA scan shows osteopenia, or low bone mineral density, “especially if they’re going on an aromatase inhibitor (or AI) which further reduces the bone density.”

In the metastatic setting, she uses them “routinely,” but said it’s imperative to “balance the side effects against the benefits.”

“With metastatic breast cancer, we are trying to preserve their quality of life,” she said. “If someone has just one site of disease, I might not strongly push it. It’s a fine balance to achieve. Women with metastatic disease will be on this drug indefinitely.”

Gralow said in early-stage post-menopausal women (including those who’ve had ovary suppression), BMAs can reduce risk of bone mets but “since many are at low risk of recurrence even if they don’t use it, we weigh the risks and benefits differently than in the metastatic setting when the risk of a bone fracture and bone pain from the met is high.”

“We’re much more cautious about using them when the risk of breast cancer recurrence is low and the risk of ONJ, for example, is elevated, as in smokers and those with poor dental health,” she said.

Cancer patients usually get higher doses of BMAs than those who take them for osteoporosis. Manohar said patients should also be aware the drugs “stay in your body for a very long time.” And with some, it’s essential to taper off, not stop suddenly. Side effects like ONJ and atypical femur fractures are “associated with more long-term use,” Manohar said, but again stressed these adverse effects are rare.

“We’re pretty good at screening before we start,” she said. “If someone has dental procedures coming up, that’s a clue to hold off or not give it.”

Photograph of breast cancer patient Dina Lorraine wearing a teal green jacket, white blouse and silver hoop earrings.

'I’ve had zero problems, not even with the first infusion.'

— Lobular breast cancer patient Dina Lorraine

The side effect spectrum

Body aches, fever and other flu-like symptoms lasting one to three days are common with the first infusion of a bone agent like zoledronic acid (marketed as Zometa or Reclast). But not for Dina Lorraine, a 53-year-old public relations executive and lobular breast cancer survivor from Seattle.

“I was put on Zometa to help keep osteoporosis away due to AIs and the added bonus of staving off bone mets,” she said.  “And I’ve had zero problems, not even with the first infusion.”

Lorraine gets an infusion every six months. She’s been on the drug nearly three years.

Abigail Johnston, a 42-year-old former lawyer and metastatic breast cancer patient advocate, was put on a BMA after being diagnosed with stage 4 disease at the age of 38.  Her kids were four and two.

“By the time the doctors figured it out and I had a CT scan, my bones looked black, there were so many mets,” she said. “My right femur was about to shatter. During chemotherapy, I had titanium rods put in both femurs.”

Along with other treatment, she had two infusions of Xgeva, or denosumab, a bone-strengthening agent also marketed as Prolia. Then she moved to Miami and her new oncologist put her on zoledronic acid, monthly at first, then quarterly.

“My oncologist had multiple patients who’d been on Zometa for decades and she believed it’s helped them stay NED (no evidence of disease),” she said.

The drugs helped her bones, but after two years, Johnston was diagnosed with bisphosphonate-induced ONJ, or BIONJ. Over the months, bits of dead bone worked themselves out through her gums. Eventually, a back molar began to loosen, and soon, was only connected by tissue.

“That’s when the pain happened,” she said. “It was so mobile, hitting all kinds of nerves. They said to try and manage as long I could. I was on a significant amount of oxycodone.”

She took pain meds for two to three months, then finally had her dentist pull the tooth. Now, she has “a hole that goes all the way down through my jawbone.” She also has a second spot where she fears she’ll lose another tooth.

Through her cancer center, Johnston connected with a palliative doctor and a maxillofacial specialist (she also sees a dentist trained in ONJ), all of whom guide her care. She uses antibiotic mouthwash multiple times a day, avoids devices like Waterpiks and said she’s “keeping Oragel in business.”

“I just have to be super, super, super careful not to do anything that would irritate the bone more, “she said. “If they operate or intervene or open anything up, you run the risk of the osteonecrosis spreading. They can’t crown it; it won’t adhere to the dead bone. Now it’s about managing the BIONJ.”

How does she feel about continuing to take a drug that’s caused such damage?

“Zometa is contributing to my longer life expectancy, which means more time with my kids,” she said. “I’d trade every tooth in my mouth for more time with them.”

Photograph of metastatic breast cancer patient Abigail Johnston in a black V-neck dress and an adorable tomato-colored vintage-style hat with veil.

'I have to be super, super, super careful not to do anything that would irritate the bone more. If they operate or intervene or open anything up, you run the risk of the osteonecrosis spreading ... Now it’s about managing the BIONJ.'

— Metastatic breast cancer patient advocate Abigail Johnston


Who’s at risk and how many?

Atrial fibrillation, kidney toxicity and atypical femur (thighbone) fractures have also been associated with BMA use, but osteonecrosis of the jaw seems to be the side effect that worries breast cancer patients the most.

“I am soooo scared of developing ONJ,” tweeted one during a discussion of side effects.  

But what are the actual odds of contracting it? A recent SWOG study, co-led by Gralow, looked at data from nearly 3,500 cancer patients treated with IV bisphosphonate or denosumab for their metastatic bone disease. Ninety cases of ONJ were confirmed. The estimated cumulative incidence, or risk of ONJ at three years was 2.8%. Rates were .08% at year one and 2% at year two. Over three years, the team found:

  • Patients with myeloma had the highest rates: 4.3%
  • Patients with more exposure to zoledronic acid had higher rates: 3.2%
  • Patients with breast cancer had the lowest rates: 2.4%
  • Patients with poor dental health had higher rates, e.g., fewer teeth: 4.4%; dentures:  5.0%; prior oral surgery: 3.8%
  • Current smokers had higher ONJ rates: 3.7%

The results pointed to the importance of optimizing oral health before initiating BMAs and slowing the dosing from monthly to quarterly.

A related study, also led by Gralow, looked at risk factors for bisphosphonate-related ONJ, or BRONJ, in early-stage breast cancer patients. They studied three BMAs, measuring time to onset, determining ONJ drivers, and incorporating BRONJ prevention guidelines, with patients completing dental procedures before BMA use; undergoing regular dental exams; using good oral hygiene, etc.

After nearly eight years of follow-up, 48 out of 6,018 women developed ONJ. That’s just 0.8%.

Participants developed ONJ with all three BMAs, but zoledronic acid use and poor dental health increased the risk, especially when combined. Median duration to onset was 2.3 years. ONJ was considered spontaneous or “unprovoked” in 20 lesions and “provoked” by dental extraction in 20; periodontal disease in 14; denture trauma in six; and other dental surgery in two. ONJ was more than twice as likely to show up on the lower jaw than the upper. People who developed spontaneous, or unprovoked, ONJ tended to heal faster.

Prevention and education key

BRONJ prevention should be “implemented widely,” the authors concluded. Further studies are also needed, they said, to design protocols to train and support medical and dental providers in preventing the condition.

Johnston, who is connected with others living with ONJ via several large private Facebook groups, agreed there’s a huge need for education on the condition — and not just among patients.

“Eighty to 90% of the people in my group get bad treatment from a dentist,” she said. “They get root canals — the dentists do it with the best of intentions — but it causes so much trauma to the jaw. They don’t understand you need to do the least possible.”

And ONJ is hardly restricted to cancer patients, she said.

“There are many people with osteoporosis in the ONJ groups,” she said. “Or they were prescribed for osteopenia. I’ve heard horror stories. Prolonged exposed to bisphosphonates is not a good idea.”

In 2012, the Food and Drug Administration cautioned patients with osteoporosis against long-term use of zoledronic acid (aka Reclast), alendronate (Fosamax) and ibandronate (Boniva), publishing an analysis prompted by reports of adverse effects. In 2018, they provided an additional safety update regarding atypical femur fractures. 

Following the science

Manohar said guidelines at SCCA have shifted to reflect the most recent studies.

“We used to give Zometa monthly but we’ve transitioned to every three months,” she said. “It’s just as good in preventing skeletal-related effects like fractures.”

What advice does she give for breast cancer patients contemplating their use?

“You have to weigh the risk of potential complications in the oral area versus complications from the cancer,” she said. “Fractures (due to metastatic bone disease) can be pretty debilitating as well.”

And the drugs can also be pricey, she said, another potentially toxic side effect.

“Zometa is not as expensive,” she said. “Maybe $170 with its administration but denosumab is $2,000 a dose. That’s a staggering difference.”

A researcher with the Hutchinson Institute for Cancer Outcomes Research, or HICOR, Manohar is currently investigating BMA use among Washington state cancer patients and studying whether de-escalating might be a way to provide more value and do less harm. A recent analysis showed doing so could save patients and payers millions of dollars.

“That’s a piece of this,” she said. “Can we de-escalate the treatment but still get the same outcome and positively impact the patient experience? They could come in less often for infusions and potentially have fewer side effects.”

As for expanding the use of these agents to patients with DCIS, she said it’s compelling research but requires further study.

“It’s definitely adds to the literature,” she said. “We do want to prevent breast cancer and anti-hormone therapy is not optimal for everyone because of the side effects. But is putting patients with DCIS on bisphosphonates going to lead to problems later on? It’s worth exploring, but with these side effects, the big question is: What’s the dose and how long do we give it?”

Diane Mapes is a staff writer at Fred Hutchinson Cancer Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at dmapes@fredhutch.org. Just diagnosed and need information and resources? Visit our Patient Care page.

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