For many years, women with breast cancer were considered to be safe from osteoporosis. The two diseases were thought to exist at opposite poles according to estrogen status: too much estrogen equaled breast cancer; too little estrogen equaled osteoporosis. As you might expect, that is not the case. Both are common problems, and there is a large overlap.
Low bone mass and an increased risk of fractures are common in women with breast cancer. This may be due to the effects of both the cancer itself and the drugs used to treat it. Management of bone health has emerged as an important part of comprehensive breast cancer care. As a result, many medical oncologists have expanded their role to include assessment of bone health as part of your care.
BONE DENSITY AND FRACTURES
Bone density measured in breast cancer survivors may be lower than normal and fracture risk is higher. This may be a consequence of treatment for breast cancer. Bone mass tends to be higher in breast cancer patients prior to treatment, but that is not always the case. Low bone density may be present before any treatment as well.
Dr. Donna Kritz-Silverstein, a colleague of mine at the University of California, San Diego, and I compared the bone density of postmenopausal women with newly diagnosed breast cancer, prior to any therapy, with age-matched normal controls. We observed little difference in bone density between women with and without breast cancer. Women were remarkably similar in all aspects of lifestyle and risk factors for osteoporosis and breast cancer. The only differing characteristic was that women with breast cancer had more body fat at their waists, a place we would all like to be trimmer!
The bottom line is that a DXA scan of your hip and spine is needed to find out your baseline bone density prior to treatment. This information will help guide management over the long-term. If one was not done as part of your initial battery of tests, don't worry. At any point in time, the bone density will be useful. If you have not had a bone density scan yet, get one at your earliest convenience.
TREATMENTS
Chemotherapy
Chemotherapy and its consequence on bone health is primarily a concern for premenopausal and perimenopausal women. Chemotherapy causes early menopause in over half of premenopausal or perimenopausal women. The abrupt loss of estrogen causes rapid bone loss, particularly in the spine. The bone in the spine responds dramatically to the lack of hormone by revving up its metabolism and breaking down bone fast. This creates a higher risk of spine fractures in later life.
This same response occurs in postmenopausal women who stop taking estrogen when breast cancer is diagnosed.
A direct harmful effect of chemotherapy on bone has been suggested but not proven. Chemotherapy given for breast cancer usually consists of a “cocktail” of ingredients. With multiple drugs, it is difficult to identify exactly which drug may be a culprit. Methotrexate, a common agent used in different chemotherapy regimens, may have a direct toxic effect on bone-formation cells, resulting in bone loss.
Radiation Therapy
Newer techniques and types of equipment used for radiation therapy do not affect the bone.
Hormonal Therapy
Not to be confused with estrogen therapy or “hormone replacement therapy,” hormonal therapy is actually antiestrogen therapy. It is usually prescribed for a five-year course after the initial breast cancer treatments.
Tamoxifen
Tamoxifen has long been the breast cancer “insurance drug” that is used for five years to prevent the reccurrence of breast cancer. Tamoxifen is a “designer estrogen.” In some parts of the body, it acts like estrogen, while in others it works as an antiestrogen. Technically, tamoxifen is called a selective estrogen receptor modulator, or “SERM” for short. In the bone, it mimics the effect of estrogen and protects against bone loss. In contrast, estrogen is blocked in the breast tissue, and breast tumor growth is prevented.
For postmenopausal women, a newer type of drug called an aromatase inhibitor is more effective than tamoxifen in preventing return of breast cancer. Since aromatase inhibitors (AIs) were adopted as standard therapy for postmenopausal women with hormone-sensitive early breast cancer, the use of tamoxifen has declined. However, because of high cost and/or inability to tolerate aromatase inhibitors, tamoxifen is still commonly used.
Tamoxifen remains the standard of care in premenopausal women with regular menstrual periods who are still making their own estrogen. In contrast to postmenopausal women, bone may be lost at an accelerated rate in premenopausal women rather than being preserved. This paradoxical effect is not completely understood. Therefore, premenopausal women using tamoxifen should have regular bone density scans every two years.
Aromatase Inhibitors
Rather than blocking estrogen's activity like tamoxifen, aromatase inhibitors actually prevent the body from making estrogen. These potent medicines dramatically reduce circulating estrogen by about 90 percent. As you might expect, this is not good for bone. Bone loss with an increased risk of fracture is the main problem with use of aromatase inhibitors.
What Are Aromatase Inhibitors?
Once your ovaries shut down with menopause, your body still produces some estrogen. The adrenal glands that sit on top of the kidneys produce androgens, the precursor to estrogen. An enzyme called aromatase is in tissues such as fat, muscle, liver, and breast. It converts the adrenal androgen to an aromatic state that is estrogen. Aromatase inhibitors (AIs) prevent the body from making this conversion to estrogen, hence the name.
Three different aromatase inhibitors are available:
| Brand | Generic Name |
| Arimidex® | anastrozole |
| Aromasin® | exemestane |
| Femara® | letrozole |
The different modes of action of aromatase inhibitors and tamoxifen explain their effects on bone. This was demonstrated in the bone substudy of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. After five years, the Arimidex-treated women lost bone in the lumbar spine (-6 percent) and total hip (-7 percent). In contrast, those on tamoxifen had stable bone density at the total hip and a modest increase at the lumbar spine (+3 percent).
In addition, the early high rate of bone loss with Arimidex at the spine appeared to slow after the second year of treatment. However, the rate of bone loss at the hip was consistent over the five years. Early postmenopausal women (within four years of their last menstrual period) had the highest rate of loss at the lumbar spine, at -11 percent after five years. No one who started with normal bone density became osteoporotic while on Arimidex. That should be reassuring; however, women with low bone mass (T-scores between -1 and -2.5) did develop osteoporosis during the five-year treatment period.
Even so, it is important to point out that the majority of fractures occur in women with low bone mass (T-scores between -1 and -2.5) who are prescribed aromatase inhibitors. In the overall ATAC trial, fractures were more common in the Arimidex-only group. Similar findings were observed in trials using the other aromatase inhibitors, Aromasin and Femara. Prevention of aromatase inhibitor-associated bone loss is key to reducing risk of low bone density and fractures.
Prevention of Aromatase Inhibitor Bone Loss
First of all, the general principles of a bone-healthy lifestyle, along with adequate calcium and vitamin D, are essential but not enough. Additional boneprotection strategies are required for women treated with aromatase inhibitors. Multiple studies have been done and more are underway with different bisphosphonates and the new “first in class drug” Prolia. The acronyms abound: BIG, AZURE, HALT, IBIS, SABRE, Z-FAST, ZO-FAST, to name a few of the trials.
In the bisphosphonate class, Actonel, Boniva, Zometa, and a drug not available in the US (clodronate) have been evaluated separately, but there are no head-to-head comparison trials. All prevent bone loss and provide good bone protection in women taking aromatase inhibitors. The bulk of the studies have been with Zometa. Note that Zometa is zoledronic acid given in a 4 mg dose intravenously (by vein), which is the same drug marketed in a 5 mg dose as Reclast, which is indicated for postmenopausal osteoporosis. The frequency of Zometa use varied in the trials. A typical course was Zometa administered intravenously every six months.
Overall, Zometa is well tolerated and takes only fifteen minutes to be given by vein. Mild flu-like symptoms may occur in the first three days after the dose. Taking two acetaminophen (Tylenol) tablets beforehand may prevent or lessen these symptoms. Some protocols may specify more extensive use of acetaminophen, such as two tablets every six hours starting the day before the infusion and continuing for two to three days. Damage to the jawbone, called “osteonecrosis of the jaw,” is a potential problem, but it is uncommon. You may lower your risk with good dental hygiene and by avoiding dental procedures that involve the bone.
Prolia (denosumab) is first in a new class of drugs designed to inhibit proteins that activate bone-destroying osteoclast cells. In the HALT (Hormone Ablation Therapy) Breast Cancer study, women with low bone mass (T-score between -1 and -2.5) who were taking aromatase inhibitors received either Prolia or placebo. Prolia 60 mg was given by a simple injection just under the skin (subcutaneous) every six months for two years. The Prolia group gained bone mass at the spine and hip and the placebo group lost bone.
Bone loss due to aromatase inhibitors is manageable with preventive therapy using bisphosphonates or Prolia. Therefore, the potential detrimental effects of aromatase inhibitors on the bone need not influence their use, which is needed to prevent breast cancer recurrence.
Other Benefits of Bone-Active Drugs: Weakening Cancer?
Exciting results show that the benefits of bisphosphonates and Prolia may extend beyond preserving bone and preventing fractures. Bone is the most frequent site of cancer relapse beyond the breast itself, called metastases.
Early studies with clodronate in Europe suggested that bisphosphonates may prevent spread of breast cancer to the bone. Bisphosphonates and Prolia create a “hostile” environment for cancer cells so they will not be attracted to the bone surface and grow. The recent data with Prolia and the potent bisphosphonate Zometa suggest that bone-targeted treatments may indeed prevent metastasis to the bone.
These potent bone drugs may also have direct effects on tumor cell growth, which modify the course of the disease. In one trial with the aromatase inhibitor Femara, Zometa was given immediately and every six months over five years or was started later for treatment of rapid bone loss or fracture. Not only was beginning treatment immediately with Zometa superior for bone protection, but fewer women had recurrence of their cancer at any site, not just the bone. The immediate versus delayed results suggest a direct antitumor effect of Zometa.
Similar results were found in the Austrian Breast Cancer Study Group (ABCSG XII), a large study of premenopausal women who took medicine to suppress estrogen produced from their ovaries. They were divided into groups that received either tamoxifen or the aromatase inhibitor Arimidex, and each of these groups was subdivided into groups that either did or did not take Zometa every six months for three years. Those receiving Zometa had 35 percent fewer distant and local recurrences. Zometa now has an FDA indication for use along with standard cancer therapies in women who have bone metastases from breast cancer. However,Zometa may not be used in patients with reduced kidney function.
Prolia (denosumab), through a different mechanism, may provide bone protection. Cancer cells appear to stimulate production of the messenger protein (RANK ligand, or RANKL) that increases osteoclast activity, resulting in local bone breakdown and skeletal complications. Prolia works by binding to the messenger protein and inhibiting its actions. Based on the bone biology, use of Prolia should counteract the effect of cancer cells and may also have a direct antitumor effect.
In studies of patients with bone metastases from solid tumors, a dose of 120 mg of denosumab was administered every four weeks. Upon FDA-approval for the prevention of skeletal-related events in patients with bone metastases from solid tumors, the brand name given for this dose of denosumab and frequency of use was “Xgeva,” which distinguishes the new formulation from the lower dose and twice-yearly administration of Prolia.
In a large study of 2,046 women with advanced breast cancer and bone metastasis, the subjects were randomized to receive Xgeva 120 mg or Zometa 4 mg every four weeks. The study monitored for “bone-related events,” which included fracture due to cancer, spinal cord compression, or need for radiation therapy or surgery to bone. Xgeva prevented more bone-related events than Zometa. Xgeva also delayed development to first bone-related events by 18 percent compared with Zometa. Although Xgeva was superior to Zometa in delaying or preventing bone-related events, overall survival, disease progression, and rates of side effects were similar between groups. In contrast to Zometa, Xgeva can be given to patients with reduced kidney function.
These results are encouraging; stay tuned for more in the near future, as current trials report their findings. Use of potent osteoporosis drugs for prevention of complications from breast cancer would be a welcome added benefit. To think they may prevent or delay the onset of metastases to other sites beyond bone and even prolong survival is mind-boggling.
GENERAL GUIDELINES
Increased awareness of the impact of breast cancer on bone health has led to increased use of preventive measures. Bone-specific therapies may play a role not only for prevention of bone loss and maintenance of bone mass but also for the added benefit of anticancer properties.
Osteoporosis medicines are being utilized more and more as part of comprehensive breast cancer care. The use of aromatase inhibitors for five years after the initial treatment of breast cancer requires careful evaluation of osteoporosis risk factors and management to prevent bone loss. Several bisphosphonates and Prolia are being evaluated for the indication of prevention of bone loss for women receiving aromatase inhibitors for breast cancer treatment.
For those breast cancer survivors who are at high risk of fracture, the options for lowering fracture risk are the same as those for women with postmenopausal osteoporosis. However, there are several cautionary notes. Estrogen should not be used at all. If you have used tamoxifen, do not use its “cousin” Evista because it could actually fuel breast cancer growth. Because of concerns about osteosarcoma, a cancer of the bone, Forteo should not be used if you have received radiation therapy.
Zometa and Xgeva (denosumab 120 mg) given every four weeks have FDA-approval for use in women with bone metastases from breast cancer. Additional effects of these medicines, such as actual antitumor effects, are under investigation.
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The Bare Bones Bone health evaluation is an essential part of comprehensive breast cancer care. Women with breast cancer at higher risk for bone loss and fractures include:
Optimize your bone health with general measures. Discuss with your physician regular monitoring of bone density and whether use of bone-specific medicines is needed. |