Aromatase inhibitors are drugs that block the production of estrogen in postmenopausal women. These drugs are commonly used in the treatment of hormone receptor-positive breast cancer, and may also have a role in breast cancer prevention—particularly in women at high risk of the disease.
A premenopausal woman who goes through chemotherapy treatment for breast cancer may experience early menopause and she is at risk for bone loss because of the shorter duration of exposure to the bone-preserving effects of estrogen.
Historically, tamoxifen was the main agent used as hormone therapy for breast cancer patients. More recently, aromatase inhibitors have demonstrated improved outcomes compared to tamoxifen.
Breast cancer patients are exposed to additional risk if they are treated with an aromatase inhibitor (AI). Postmenopausal women with estrogen receptor-positive (ER-positive) breast cancer are highly likely to be treated with an AI. These drugs cause bone loss by reducing the amount of estrogen in the body and include2
Aromatase inhibitors are drugs that block the production of estrogen in postmenopausal women.
- Arimidex® (anastrozole)
- Aromasin® (exemestane)
- Femara® (letrozole)
Arimidex, as well as other aromatase agents, is commonly used in the treatment of postmenopausal, hormone-positive breast cancer.
Women who are treated with the aromatase inhibitor Arimidex® (anastrozole) for 5 years experience bone loss. Results from the ATAC trial, in which postmenopausal women with hormone-positive, early breast cancer were treated with Arimidex or Nolvadex® (tamoxifen) for five years found that women taking Arimidex had a 6%-7% loss of bone mineral density and a fracture rate of 11%. The risk of bone fractures declined once women stopped taking Arimidex.
Reference: Coleman R, et al. Effect of anastrazole on bone mineral density: 5-year results form Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. June 2006. Atlanta, GA. Abstract 511.
Aromasin® (exemestane) also reduces the risk of breast cancer but increases bone loss. Although aromatase inhibitors such as Aromasin provide breast cancer benefits, these drugs have also been reported to adversely affect bone. To explore the effects of Aromasin on bone among healthy women who use the drug for breast cancer prevention, researchers evaluated a subset of the women who participated in the MAP.3 trial. Information was available about 242 potmenopausal women who had been followed for two years.
During two years of treatment, bone density at the distal radius (wrist) decreased by 1.8 percent among women in the placebo group and by 6.1 percent among women in the Aromasin group. These results demonstrate that use of Aromasin by healthy postmenopausal women increases bone loss. The benefit of Aromasin for breast cancer prevention will need to be weighed against its harmful effects on bone.
 Cheung AM, Tile L, Cardew S et al. Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial. Lancet Oncology. Early online publication February 7, 2012.
Women with breast cancer who switch from tamoxifen (Nolvadex®) to Aromasin®(exemestane) have an increased risk of bone fractures but overall survival is improved with Aromasin.
Researchers affiliated with the Intergroup Exemestane Study (IES) recently conducted a subgroup analysis on the effects of Aromasin on bone health of women with breast cancer. The IES was a large trial that included postmenopausal women with early, hormone-positive breast cancer who were initially treated with tamoxifen. One group of patients in this trial continued therapy with tamoxifen, while the other switched to Aromasin. Overall, women who switched to Aromasin had improved survival compared to women who remained on tamoxifen.
However bone mineral density was lowered in women who switched to Aromasin. At 58 months 7% of patients who switched to Aromasin had developed bone fractures compared with 5% who continued to stay on tamoxifen. No patients with normal bone mineral density at the initiation of the trial developed osteoporosis.
Patients who switch to aromatase inhibitors such as Aromasin may wish to speak with their physician regarding their treatment options and potential effects on bone health.
Reference: Coleman R, Banks L, Girgis S, et al. Skeletal effects of exemestane on bone mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the intergroup exemestane study (IES): a randomised controlled study. Lancet Oncology [early online publication]. January 24, 2007. DOI: 10.1016/S1470-2045(07)70003-7.
By contrast, in postmenopausal women the drug tamoxifen (Nolvadex®) in effect replaces estrogen in the body and has a protective effect on bone similar to that of estrogen.3,4 In premenopausal women, however, for reasons that are not entirely clear, tamoxifen can cause bone loss.3
It’s important for both patients and their doctors to be aware of the bone-health effects of these drugs. Patients should have a Bone Mineral Density (BMD) test before beginning treatment with an AI and annually while on the medication.4 Getting enough calcium, vitamin D, and weight-bearing exercise is also important for all postmenopausal women who want to maintain their bone health, and this is of even greater importance for women taking AIs.
Prevention & Treatment of Osteoporosis
Osteoporosis is a condition associated with an increased risk of bone fracture. The increased risk is related to a decrease in the amount of calcium in bones causing a weakening of bone structure. With decreased bone quality, individuals are at increased risk of spontaneous fractures as well as those associated with falls. A primary location for fracture is the lumbar and thoracic spine. Other skeletal structures at risk include the hips, pelvis, and wrists.
The first step in treating osteoporosis is to prevent it by taking measures to avoid bone loss and maintain strong bones. The following measures may contribute to long-term bone health. (5,6,7)
Post-Menopausal Breast Cancer Survivors Have Increased Risk of Fractures
Post-menopausal women who have survived breast cancer are at increased risk for fractures.
Reference: Chen Z, Maricic M, Bassford T. et al. Fracture Risk Among Breast Cancer Survivors. Archives of Internal Medicine. 2005; 165: 552-558.
No Significant Bone Density Differences Between Aromasin and Arimidex
There was no significant difference in bone mineral density loss among women with early breast cancer treated with adjuvant Aromasin® (exemestane) or Arimidex® (anastrozole), according to the results of a study published in The Lancet Oncology.
Some have speculated that Aromasin, a mildly androgenic steroid, may be less detrimental to bone than non-steroidal Arimidex.
The researchers concluded that there is no significant difference in bone mineral changes among women treated with Aromasin and Arimidex. They note that their results demonstrate that adjuvant treatment with aromatase inhibitors can be used in patients with T-scores less than2.0.
Goss PE, Hershman DL, Cheung AM, et al: Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. The Lancet Oncology. Published early online March 11, 2014. doi:10.1016/S1470-2045(14)70035-X
Weight-bearing exercising, like walking, is essential to increasing or maintaining bone mineral density at any age. Also, impact or resistance exercise, such as lifting weights, is positive for bone health. These efforts will blunt bone loss but will not fully prevent it.
Calcium and Vitamin D
Calcium and vitamin D are essential to maintain bone health. Calcium is an essential building block of bone. Vitamin D is required for adequate absorption of calcium from the gastrointestinal tract.
Calcium—Dietary calcium may help combat low bone mass and reduce the risk of osteoporosis. Recommended food sources of calcium include low-fat dairy products (such as milk, cheese, and yogurt); dark, leafy green vegetables (such as broccoli and spinach); sardines and salmon with the bone; foods fortified with calcium (such as orange juice and cereals). Calcium needs change throughout life, with a greater demand occurring during childhood and adolescence, during pregnancy and breastfeeding, and in postmenopausal women and older men. For example, 1,300 mg/day of calcium is recommended for children and adolescents age 9 to 18 years, and 1,200 mg/day is recommended for adults age 51 and older.8
Debate has surfaced regarding the appropriate daily intake of calcium. Current recommendations suggest 600 mg of calcium with any remainder from dietary sources including dairy products, like milk or yogurt, and vegetables, like broccoli. A variety of calcium supplements are available. Calcium citrate is more easily absorbed. Calcium carbonate is another form of calcium supplement.
Vinegar test A vinegar test is a good means to determine if you calcium supplement is absorbable in the gastrointestinal tract. Place your calcium pill in about a quarter cup of vinegar and swirl it around. If in 30 minutes the pill has not dissolved, throw the supplement out and obtain a brand-name product. If it does not dissolve in the vinegar, it will not dissolve in your stomach and will go all the way through without any absorption.
Vitamin D Vitamin D contributes to calcium absorption as well as bone health. The body makes vitamin D through exposure to sunlight (15 minutes per day is recommended), and it can also be found in food sources including egg yolks, saltwater fish, and liver. Vitamin D supplements may be suggested for people who cannot get adequate sun exposure.
The dose of vitamin D varies depending on the level in the bloodstream. Vitamin D is made in our skin when exposed to the sun. The difficulty is that northern latitudes do not have strong enough sun exposure to produce vitamin D year round. Most medical experts recommend a daily intake of between 400 and 800 international units (IU) of vitamin D.4 Recently updated recommendations for daily vitamin D consumption by adults 50 and over is between 800 and 1,000 IU.9 Vitamin D can be quantified with blood tests. Calcium and vitamin D are prerequisite therapies for the other therapies administered for osteoporosis. The risk of side effects with other agents is increased in the absence of these supplements.
Individuals should also avoid smoking and excessive alcohol use, as these behaviors are associated with weaker bones and increased risk for fracture.
Hormone Replacement Therapy
Estrogen deficiency after menopause leads to bone loss. The greatest rate of bone loss occurs in the first years after ovarian failure. Estrogen replacement therapy or ERT has been successfully used in postmenopausal women. Replacement estrogen can maintain bone mineral density but cannot increase density in women who are already osteoporotic. The Women’s Health Initiative, a large study of estrogen and progesterone replacement therapy reported an increase in cardiovascular disease and breast cancer in women on ERT. Some women have severe estrogen deficiency symptoms including hot flashes continue to take small amounts of estrogen which may have some effect on BMD.
Hormone replacement therapy is no longer routinely recommended to treat bone loss because two large studies have shown that it increases the risk of heart attack, stroke, and breast cancer.10,11 “But if a woman is on HRT for other reasons—such as to treat menopausal hot flashes—it will prevent the rapid bone loss than can occur around menopause.” All postmenopausal women should discuss the benefits and the risks of HRT with their doctor.
The role of ERT remains an individual choice between a patient and their physician.
Evista (Raloxifene) is a selective estrogen receptor modulator with estrogen-like effects on bone resorption but without stimulating the lining of the uterus or breast tissue. The drug is administered as orally once a day. Clinical studies have demonstrated increased BMD in the spine but less in the hips. Side effects from the medicine include blood clots, leg cramps, and hot flashes.
Prolia (Denosumab) Rank ligand (RANKL) is a protein signal to osteoclasts to become active. The result is a loss of bone mineral density. Antibodies that block RANKL prevent the activation of osteoclasts thereby increasing bone mineral density. Prolia is a RANKL fully human antibody that binds to the protein. Prolia is administered as a subcutaneous injection once every 6 months. The beneficial effects can be detected within hours of the injection. Injections need to be repeated to have a sustained benefit. The full duration of Prolia therapy remains to be determined. Potential toxicities are similar to those of bisphosphonates including bone pain, osteonecrosis of the jaw and atypical fractures of the femur. An additional risk is that of cellulitis or other infections in individuals who are taking immunosuppressive agents like anti TNF antibody therapy.
Prolia Approved for Treatment of Bone Loss in Patients with Breast or Prostate Cancer
The U.S. Food and Drug Administration (FDA) has expanded the approval of Prolia® (denosumab) to include treatment of bone loss among breast cancer patients treated with aromatase inhibitor therapy and prostate cancer patients treated with androgen deprivation therapy for non-metastatic cancer. Treatment is intended to increase bone mass among patients at high risk of fracture.
Osteoporosis affects an estimated 10 million Americans over the age of 50. Each year, roughly 1.5 million Americans will experience an osteoporosis-related bone fracture. These fractures commonly involve the wrist, hip, or spine, but can affect any part of the body.
Bone loss accelerates as we age (with particularly rapid loss in women after menopause), but can also be caused by certain types of cancer treatment. Hormonal therapies such as aromatase inhibitors for breast cancer and androgen-deprivation therapy for prostate cancer, for example, are known to cause bone loss. Bone loss from cancer treatment tends to be more rapid and severe than the bone loss that occurs naturally with aging.
Prolia targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Prolia has been shown to reduce the risk of fractures in high-risk postmenopausal women with osteoporosis, and was approved for this purpose in 2010.
Studies have also now shown that Prolia is effective against cancer treatment-induced bone loss. In a study of men undergoing androgen-deprivation therapy for non-metastatic prostate cancer, those who received Prolia were 62% less likely to develop a new vertebral fracture than those who received a placebo.Prolia has also been found to improve or maintain bone density among women undergoing aromatase inhibitor treatment for breast cancer. The most common side effects of Prolia were joint and back pain.
Prolia is the first drug approved for cancer treatment-induced bone loss.
 U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General, 2004.
 Smith MR, Egerdie B, Hernandez Toriz N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. New EnglandJournal of Medicine. Early online publication August 11, 2009.
 Ellis GK, Bone HG, Chlebowski R et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. Journal of Clinical Oncology. 2008;26:4875-4882.
Bisphosphonates are the most commonly prescribed therapy for osteoporosis. The concept behind these medicines was the interaction between detergents and hard water. Bisphosphonates are similar in structure to a component of bone. Osteoclasts are the cells that break down bone during the remodeling process. Bisphosphonates attach to the active sites on osteoclasts and prevents their activation. By decreasing bone reabsorption bone mineral density is increased by allowing a preference to the osteoblast bone forming cells. The effect on density is rapid within months.
The toxicities of oral bisphosphonates are greatest on the gastrointestinal tract with esophageal irritation. They also have poor intestinal absorption. The drug is taken in the morning after an overnight fast, with a large glass of water. Remaining upright for 30 minutes is necessary to decrease the risk of to the esophagus. With movement of calcium into bones, muscles may become calcium deficient resulting in persistent cramping. Bone and joint pain may also occur.
Fosamax (Alendronate) is a bisphosphonate, taken orally on a weekly basis. Fosamax has beneficial effects on bone mineral density in the spine and hip. The effect on bone is prolonged. Bone mineral density may increase by 5% to 10% over 2 to 4 years and reduce fracture risk by 30% to 50%. The optimal duration of therapy has not been determined.
Actonel is a bisphosphonate taken weekly at 35 mg or 150 mg once a month. The drug increases bone mineral density in hips and spine.
Boniva (Ibandronate) can be administered orally or intravenously. The oral form is given monthly in a 150 mg dose given the same day of the month. The intravenous form is given by vein, 3 mg/3ml every 3 months. The benefits on spine and hip are similar to other bisphosphonates as are the side effects.
Reclast (Zolendronic Acid) is an intravenous form of bisphosphonate administered once a year. Reclast reduces hip and spinal fractures and increases bone mineral density. Infusions may be given for 3 years. Infusions, given over 15 minutes or longer, are usually well tolerated with about 20% having 3 days of muscle or bone pain. A much smaller group of patients may develop a severe bone pain syndrome that can last for months.
Osteonecrosis of the Jaw Another potential side effect associated with all bisphosphonates is osteonecrosis of the jaw. Osteonecrosis is an area of bone where cells have died. The result is an area of bone that will disintegrate. The risk for jaw osteonecrosis increases if dental repairs are conducted after bisphosphonate therapy is established. Risk is increased the longer an individual takes bisphosphonates. A recommendation is given to have dental work completed before initiating bisphosphonate therapy. The risk of jaw necrosis is small in most individuals taking bisphosphonates. Intravenous forms of bisphosphonates are more closely associated with this toxicity.
Human Parathyroid Hormone is a naturally occurring protein associated with maintaining blood levels of calcium. The source of calcium is bone. When present in persistent levels, bone loss occurs. When bone is exposed to small amounts, a contrary effect occurs on osteoblasts, causing a building of bone.
Teriparatide (Forteo) is an injectable form of parathyroid hormone. A daily injection into the abdomen or thigh of 20 mcg for 2 years is associated with significant improved bone density in the spine and the hip. The drug is limited to a 2 year administration because longer duration of therapy is associated with the development of cancer in rats. This form of therapy is indicated for those individuals with previous fractures or inability to tolerate bisphosphonates. Toxicities associated with this injectable therapy include dizziness and nausea.
Calcitonin is a natural hormone that reduces bone breakdown in the human body. The hormone is produced by the C cells in the thyroid gland. The hormone is effective in decreasing the risk of fracture in the spine, but not as much in the hip. Women five years post-menopausal who are unable to take bisphosphonates are candidates for this drug. Men with normal testosterone levels are also responsive to this agent. Calcitonin harvested from salmon is used as a nasal spray as a therapeutic agent for mild osteoporosis. The recommended dose of calcitonin salmon nasal spray is 1 spray (200 units) per day alternating nostrils daily. Side effects include nasal irritation and a small, increased risk of malignancy 4% versus 2% in normal populations.
- Chen Z, Maricic M, Bassford TL, et al. Fracture risk among breast cancer survivors: Results from the Women’s Health Initiative Observational Study. Archives of Internal Medicine. 2005;165(5):552-58.
- Shapiro CL. Aromatase inhibitors and bone loss: Risks in perspective. Journal of Clinical Oncology.2005;23(22):4847-49.
- Van Poznak C, Sauter NP. Clinical management of osteoporosis in women with a history of breast carcinoma. Cancer. 2005;104(3):443-56.
- Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. Journal of Clinical Oncology.2003;21(21):4042-57.
- The National Institutes of Health Osteoporosis and Related Bone Diseases ~ National Resource Center
- National Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse National Institutes of Health
- National Osteoporosis Foundation
- Prevention: Calcium Supplements. National Osteoporosis Foundation Web site. Available at http://www.nof.org/prevention/calcium_supplements.htm.
- Prevention: Calcium and Vitamin D. National Osteoporosis Foundation Web site. Available at http://www.nof.org/prevention/calcium.htm.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association. 2002;288(3):321-333.
- Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association. 2004;291(14):1701-12.