It's Complicated: Maintaining Healthy Bones Against All Odds

FOLLOWING THE START of menopause, Karen Roberts was put on Arimidex and now has osteopenia. - PHOTO BY BOB RIVES

Karen Roberts of Washington, D.C., was 53 in 2009 when she was diagnosed with stage 2b breast cancer. Her tumor had both estrogen- and progesteronepositive receptors. In consultation with her doctors, she opted for a full mastectomy on one side, followed by 24 weeks of chemotherapy and six weeks of radiation.

Although many women go into menopause after treatment, Roberts remained perimenopausal — her body was making the natural transition to menopause. To prevent a recurrence of her cancer, Roberts began adjuvant endocrine therapy, also called hormonal therapy.

Since she was perimenopausal, her doctors prescribed tamoxifen, which is part of a class of drugs called selective estrogen receptor modulators. These drugs work by blocking estrogen’s effects in the breast, which helps slow the growth and reproduction of breast cancer cells. Although tamoxifen has many side effects — hot flashes, loss of sex drive, vaginal discharge and vaginal dryness or itching — it also has an estrogen-like effect on the bones, which has proven to be beneficial for postmenopausal women. Among these women, tamoxifen can improve bone density and help prevent osteopenia and osteoporosis.

Roberts took tamoxifen for five years. Once a year, she was given a bone density screening test to make sure her bones showed no signs of thinning. The treatment proved effective at both keeping the cancer at bay and maintaining her bone health.

Then Roberts went through menopause, so her treatment plan changed. For the past 2 ½ years, she has been taking Arimidex (anastrozole), an aromatase inhibitor that prevents the formation of the female hormone estradiol. Although Roberts remains cancer-free, the combination of becoming menopausal and taking Arimidex has taken its toll.

“My last bone density screening found that I now have osteopenia,” Roberts says. “I was really surprised, because I had been taking vitamin D and calcium to build up my bones. Also, I’m overweight, putting me at a slightly reduced risk. I don’t need any bone-protecting medications yet, but I do need to pay attention.”

Roberts is not alone. According to the National Osteoporosis Foundation, even within the general population, 1 in 2 women aged 50 years or older is at risk of a fracture due to osteoporosis in their lifetime. For postmenopausal women taking an aromatase inhibitor, the rate of bone loss increases from 1 percent to 2 percent each year. This small increase is enough to increase the risk of fracture.

THE ART AND SCIENCE OF TREATMENT MANAGEMENT

Knowledge about prescribed medications, their possible effects on the bones and how to address side effects offers the best defense against potentially devastating bone issues.

Bones are living tissue, and they continuously engage in formation and resorption. In healthy, young bones, these two processes are balanced. Problems arise when bone resorption exceeds formation. This often occurs with aging, and some medications can accelerate the process. Sometimes the result is osteopenia, or low bone mineral density. This mild to moderate thinning of the bone mass can progress to osteoporosis, a condition characterized by even lower bone mass, deterioration of bone tissue, disruption of the bones’ overall structure and an increased risk of fractures.

“The impact of cancer treatment on the bones varies by the type of cancer and its therapy,” says Catherine Hall Van Poznak, M.D., associate professor at the University of Michigan in Ann Arbor and an expert in bone health. “For example, cervical cancer is not an estrogen-sensitive tumor cell, so anti-estrogen therapy is not involved in its management, but women who have had radiotherapy may be at risk for bone fractures in the treated area. Endocrine therapy for uterine cancer is not well studied for bone health.

Premenopausal women who have had their ovaries removed experience premature menopause associated with a greater risk of osteoporosis. The largest group of women at risk for treatment-related bone loss are those with breast cancer. About 75 to 80 percent of this population have tumors fueled by hormones, so anti-estrogen treatments are used to prevent recurrence.”

The options available are tamoxifen, which is approved for both pre-, peri- and postmenopausal women, and aromatase inhibitors, including Arimidex, Aromasin (exemestane) and Femara (letrozole), which are effective only in postmenopausal women. Aromatase inhibitors are particularly deleterious to bones because of the affect they have on the levels of circulating estrogen that come from the adrenal glands, which makes androgen. The enzyme aromatase converts androgen to estrogen, but the aromatase inhibitors block the conversion from taking place. The effect of this treatment is to lower the amount of circulating estrogen.

Nonetheless, aromatase inhibitors are the treatment of choice for postmenopausal women with hormone-related, early-stage breast cancer, largely because of the findings from many studies comparing them with tamoxifen. For example, in 2005, a large clinical trial referred to as ATAC (Arimidex, Tamoxifen, Alone or in Combination), compared the effectiveness of the aromatase inhibitor Arimidex with tamoxifen among 9,366 postmenopausal women with localized breast cancer. The results showed that Arimidex compared with tamoxifen significantly prolonged diseasefree survival and time to recurrence, as well as significantly reduced local recurrences and distant metastases.

Although the study had a protocol that documented that bone loss was greater with Arimidex than with tamoxifen, it has taken widespread use of aromatase inhibitors to highlight the impact of these medications. Widespread use of aromatase inhibitors has revealed that these issues can be problematic and, over time, fracture rates clearly are higher with aromatase inhibitors compared with tamoxifen. In addition, joint pain is more common with aromatase inhibitors for reasons that are not well understood.

Given the biological profile of aromatase inhibitors, “it makes sense [that] we’re seeing more cases of fractures and osteoporosis,” notes Carolyn Crandall, M.D., M.S., a primary care physician and professor of medicine at the University of California, Los Angeles. “They are very potent drugs that bring estrogen levels way down.”

Deciding which therapy to use is “as much an art as a science,” according to Patricia Ganz, M.D., director of Cancer Prevention and Control Research at the UCLA Jonsson Comprehensive Cancer Center. “If a woman has good bones based on an initial bone density scan and has a large tumor with a higher risk of recurrence, aromatase inhibitors may be the right choice. On the other hand, if she is not tolerating the aromatase inhibitors well and is at low risk for blood clots, tamoxifen may work better. The goal is for women to stay on endocrine therapy for 10 years, so it’s essential to find one that they can tolerate over the long haul,” Ganz says.

Crandall agrees, adding that each woman is unique and should be carefully assessed based on her risk factors. “There’s no reason to think that every woman starts out with bad bone density or to jump the gun and assume that every woman is at an increased risk for fractures,” she says. “Some women are at a higher risk based on family history, parental history of hip fracture and body type, with slender women being at somewhat higher risk.”

Taking these factors into account helps determine how often to conduct scans, too. Crandall points out that women should stick with one facility for their scans. Each machine has its own idiosyncrasies, so getting scanned by the same one from year to year makes it easier to compare results accurately.

To help put all these pieces together, Crandall uses the Fracture Risk Assessment Tool (FRAX), a calculator developed by the World Health Organization Collaborating Centre in the United Kingdom and is recommended by clinical osteoporosis guidelines to determine whether a woman is at high risk of bone fractures. “It is helpful in making decisions about breast cancer treatment,” Crandall says.

The trajectory of Jennifer Morrison’s treatment plan illustrates the nuances involved in managing medications following breast cancer treatment. Diagnosed in 2013 with two different cancers in each breast, one at stage 1 and the other at stage 2, she opted for a double mastectomy and a full hysterectomy. The treatment put the then 44-year-old into menopause, so her oncologist, Julie Gralow, M.D., director of Breast Medical Oncology at Seattle Cancer Care Alliance, first tried Arimidex. When Morrison’s initial bone screening showed osteopenia in both hips, Gralow added infusions of Zometa (zoledronic acid), a bisphosphonate, once a year. These drugs not only help prevent bone loss but, according to results of recent studies, might prevent recurrences in postmenopausal patients with breast cancer. (For more information about the latest findings on the role of bisphosphonates in breast cancer treatment, see “Old Drug, New Tricks” in the CURE® October 2017 special issue on breast cancer.)

JENNIFER MORRISON developed joint pain and arthritis in her hands after taking Arimidex. - PHOTO BY SY BEAN

But Morrison soon experienced side effects from Arimidex. “I developed joint pain and arthritis in my hands,” she says. “In fact, one doctor said that my hands looked like they belonged to a 70-year-old, not a woman in her 40s. It was so bad that at one point I could barely hold a toothbrush.”

Gralow took her off Arimidex and put her on Aromasin. Since then, Morrison has noticed improvement in her hands. As for the infusions of Zometa, Morrison felt sick after the first one, but she and Gralow soon discovered that she did much better if the rate of infusion was slow.

With these adjustments, Morrison is moving better and has less joint pain. She has even started taking a Spin class — the high impact further supports her bones while on Aromasin.

STRATEGIES FOR STAYING HEALTHY

Another option for patients is Prolia (denosumab), which may improve survival and cut the risk of bone issues. The drug was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture and to increase bone mass in women who may be at risk for fracture after adjuvant aromatase inhibitor therapy.

In addition to following an appropriate medication regimen, women can protect their bones by living a healthy lifestyle. For example, eating nutritious foods, including those high in calcium; drinking small amounts of alcohol; and not smoking.

Although the data are mixed about whether vitamin D and calcium supplements decrease the risk of fractures — the latest study from the Journal of the American Medical Association indicates that supplements don’t make a difference — the National Osteoporosis Foundation recommends that women aged 51 and older take 1,200 milligrams of calcium each day and that individuals aged 50 and older take 800 to 1,000 international units of vitamin D a day. Most clinicians agree and prescribe these supplements for their patients who do not consume these quantities in their diet.

Exercise, too, has known benefits for promoting bone health. In particular, weight-bearing exercises such as squats, lunges and stair-climbing help build bone density. “But any form of exercise can help improve balance, reduce fractures and minimize falls,” Gralow says. “Swimming and yoga improve muscle strength and coordination.”

Hawley Almstedt, Ph.D., an exercise physiologist and registered dietician at Loyola Marymount University in Los Angeles, conducted a small pilot study, Improving Physical Activity After Cancer Treatment, to determine the effect of an exercise program tailored for cancer survivors. The 13-week plan incorporated walking, core-strengthening moves and weight-bearing exercises. Although the study’s duration was too short to reveal widespread changes in bone density, many participants showed improvement in bone health at the femoral neck. A follow-up study that was twice as long showed significant improvements in bone mineral density throughout the body. These findings point to the potential of exercise in helping women improve their bone health.

“What I learned from both studies is that there is a general lack of awareness about bone health following cancer treatment,” Almstedt says. “There also is a need for more guidance on the types of exercise that work best for this population.”

Some women already have discovered how life-changing exercise can be. More than 20 years ago, a group of women cancer survivors in Seattle decided to participate in a triathlon and asked Gralow if she would serve as their physician. The experience had a profound effect on her, leading to the formation of Team Survivor Northwest, which helps women who are striving to make healthy lifestyle choices following cancer treatment. It also serves as a support group, where women meet other women, find an exercise partner or get help training for an event.

“I saw firsthand how empowering exercise was for women who had been through surgery, radiation and chemotherapy,” Gralow says. “Women start losing weight and feel better about their body image and themselves. They set manageable goals and succeed. I have seen amazing turnarounds in women’s lives.”