by Dr. C. H. Weaver M.D. updated 10/2021
Premenopausal women who go through chemotherapy treatment for 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.
Aromatase inhibitors (AI) 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. AI use increases the risk of osteoporosis.
Osteoporosis is a disease of the bones that happens when you lose too much bone, make too little bone, or both. Osteoporosis is 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.
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.2 Breast cancer survivors have an elevated risk of osteoporosis and bone fractures.3
Premenopausal women who go through chemotherapy treatment for breast cancer may experience early menopause and are at risk for bone loss because of the shorter duration of exposure to the bone-preserving effects of estrogen.3
Postmenopausal women with hormone receptor-positive breast cancer are often treated with Tamoxifen or Aromatase inhibitors which are drugs that block the production of estrogen. Aromatase inhibitors have demonstrated improved outcomes compared to tamoxifen.
Aromatase inhibitors are also often used for breast cancer prevention—particularly in women at high risk of the disease. Aromatase inhibitors cause bone loss by reducing the amount of estrogen in the body and include.
For example, women who were treated with the AI Arimidex® for 5 years in the ATAC clinical trial in early stage breast cancer 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.4
Another trial evaluated the effects of Aromasin on bone among healthy women who used the drug for breast cancer prevention in the MAP.3 trial. 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.5,6
Prevention & Treatment of Osteoporosis
The first step in treating osteoporosis is to prevent it by taking measures to avoid bone loss and maintain strong bones. It’s important for both patients and their doctors to be aware of the bone-health effects from breast cancer treatment.
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. The following measures may contribute to long-term bone health.7-13
Exercise: 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 your 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) 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.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
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.
Medications for Osteoporosis
There are several medications used for the treatment and prevention of osteoporosis.
Prolia (Denosumab): Prolia targets a protein known as the RANK ligand which signals osteoclasts to become active. Osteoclasts are cells that break down bone and increasing their activity results in a loss of bone mineral density. Antibodies that block RANKL prevent the activation of osteoclasts thereby increasing bone mineral density.
Prolia has been demonstrated in clinical trials to increase bone mass and reduce the risk of bone fracture among patients at high risk of fracture including high-risk postmenopausal women with osteoporosis and cancer patients with treatment-induced bone loss in women undergoing aromatase inhibitor treatment for breast cancer.14,15 Prolia is administered as a subcutaneous injection once every 6 months. The most common side effects of Prolia were joint and back pain.
Evista (Raloxifene): Evista 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.
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 is another potential side effect associated with all bisphosphonates. 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.
- 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.
- Body JJ. Prevention and treatment of side-effects of systemic treatment: bone loss. Annals of Oncology. 2010; 21(supplement 7):vii180-vii185.
- Chen Z, Maricic M, Bassford T. et al. Fracture Risk Among Breast Cancer Survivors. Archives of Internal Medicine. 2005; 165: 552-558.
- 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.
- Moss PE, Ingle JN, Ales-Martinez JE et al. Exemestane for breast-cancer prevention in postmenopausal women. New England Journal of Medicine. 2011;364:2381-91.
- 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.
- 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
10.Prevention: Calcium Supplements. National Osteoporosis Foundation Web site. Available at https://www.nof.org/prevention/calcium_supplements.htm
11.Prevention: Calcium and Vitamin D. National Osteoporosis Foundation Web site. Available at https://www.nof.org/prevention/calcium.htm
12.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.
13.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.
14.Smith MR, Egerdie B, Hernandez Toriz N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. New England Journal of Medicine. Early online publication August 11, 2009.
15.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.