Osteoporosis – Bone Loss and Breast Cancer

Cancer survivors have an elevated risk of osteoporosis and fractures.1 A premenopausal woman who goes through chemotherapy 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.

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

  • Arimidex® (anastrozole)
  • Aromasin® (exemestane)
  • Femara® (letrozole)

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

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 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.

Bisphosphonates

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.

References:

  1. 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.
  2. Shapiro CL. Aromatase inhibitors and bone loss: Risks in perspective. Journal of Clinical Oncology. 2005;23(22):4847-49.
  3. Van Poznak C, Sauter NP. Clinical management of osteoporosis in women with a history of breast carcinoma. Cancer. 2005;104(3):443-56.
  4. 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.
  5. The National Institutes of Health Osteoporosis and Related Bone Diseases ~ National Resource Center
  6. National Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse National Institutes of Health
  7. National Osteoporosis Foundation
  8. Prevention: Calcium Supplements. National Osteoporosis Foundation Web site. Available at http://www.nof.org/prevention/calcium_supplements.htm.
  9. Prevention: Calcium and Vitamin D. National Osteoporosis Foundation Web site. Available at http://www.nof.org/prevention/calcium.htm.
  10. 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.
  11. 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.

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