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Bone Health in Young Women Diagnosed With Breast Cancer

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 Antonella Rastelli

From the February 2010 issue of YWBCP magazine
By Antonella Rastelli, MD
Assistant Professor of Medicine
Washington University School of Medicine

Once a woman is diagnosed with breast cancer her bone health must be considered at the very beginning of therapy as breast cancer medications can negatively affect the bones. Two-thirds of breast cancers are dependent on estrogen and therapy is targeted precisely against this hormone. The most effective anti-estrogen therapy prescribed today causes bone loss and an increased risk of fractures. Moreover, young, premenopausal women will often develop ovarian failure as a consequence of chemotherapy or will be given medications to induce menopause. An important and overlooked cause of bone loss is vitamin D deficiency/insufficiency, a condition which affects close to 70-80% of women with breast cancer.

Let us first review the physiology of the bone and how estrogen and anti-estrogen therapy affects its cells. We will then discuss the effect of chemotherapy on bones in young women and present recent data from studies of drugs designed to prevent bone loss. We will learn about the importance of Vitamin D for bone health and finally discuss what women can do to maintain strong and healthy bones. A lot to cover as you can see!

Bone Physiology
The skeleton is a unique organ because it continually remodels throughout our lives. Every 7 to 8 years we have a brand new skeleton. This remodeling is achieved thanks to the constant and balanced activity of two groups of cells in the bone: the osteoclasts and the osteoblasts. Osteoclasts resorb or break down bone cells and osteoblasts direct bone formation by laying new bone matrix. In a premenopausal woman there are about 3 million resorption/formation units at work at any given time. With menopause and its associated rapid decline in estrogen, the bone resorption/formation units double. In the absence of estrogen, the osteoclasts become much more active and the osteoblasts cannot keep up with this increased resorptive activity. The imbalance between the osteoclasts and osteoblasts explains why with menopause women start to experience a decline in bone mass. To treat and prevent postmenopausal bone loss, women with osteopenia and osteoporosis have been treated with oral bisphosphonate therapy (Fosamax, Risedronate, Ibandronate) or with the intravenous form (Zoledronic Acid). Bisphosphonates work by blocking osteoclastic activity and therefore block bone resorption. However, these drugs cannot be given indefinitely. It is currently not known when a woman should stop taking these drugs so the bones may begin to remodel.

Bone, Estrogen and Antiestrogen Therapy
Breast and bone health are closely linked because both tissues respond to estrogen, but in very different ways. Estrogen is an excellent bone agent that effectively prevents bone loss and reduces the risk of fractures, but can negatively impact breast health and increase the risk of breast cancer. The mainstay of therapy for estrogen-receptor positive breast cancer hinges on antagonizing the effects of estrogen in breast tissue. For decades Tamoxifen has been the gold standard antiestrogen therapy. In recent years, a new class of drugs, called aromatase inhibitors (Anastrozole, Letrozole and Exemestane), are increasingly being used to treat postmenopausal women. This class of drugs has been shown in numerous clinical studies to be superior to Tamoxifen in reducing the risk of breast cancer recurrence without an associated increased risk of uterine cancer and blood clots. Aromatase inhibitors (AIs) work by decreasing estrogen levels by as much as 99% and are associated with an increased risk of bone loss and fractures. A healthy postmenopausal woman is expected to lose 1% of bone mineral density annually, in contrast women treated with an AI have a 2% loss in bone mineral density per year. The effect of AIs on bone loss was established in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial in which an incidence of fractures was noted to be higher in the Anastrozole arm compared with the Tamoxifen arm. Other studies using Exemestane and Letrozole have shown similar findings.

Chemotherapy-Induced Ovarian Failure and Bone Health
Managing the bone health in young women diagnosed with breast cancer is critical as many premenopausal women will develop chemotherapy-induced menopause. Cancer therapies can in fact cause ovarian failure leading to bone loss and an increased risk for osteoporosis at a younger age. Alkilating agents, particularly cyclophosphamide, can cause changes in the ovaries. Women younger than 30 who receive cyclophospamide may continue to have their menstrual periods, but 40% of women younger than age 40 experience chemotherapy-induced amenohrrea and 70-90% of women 40 and older will experience ovarian failure. The rapid loss of estrogen production in premenopausal women with chemotherapy-induced menopause, can cause on average a 4% decrease in bone mineral density in the lumbar spine within the first six months. For a woman who undergoes surgery, radiation, or chemical ovarian ablation, a loss as high as 13% in the bone mineral density may occur in the first year.

How Can We Prevent  Bone Loss
A number of studies are now underway assessing the benefit and safety of zoledronic acid in preventing bone loss in women on AI therapy. Zoledronic acid has also been studied in premenopausal women receiving chemotherapy. In a recent study, 101 women were randomly assigned before starting chemotherapy to receive zoledronic acid or placebo (no drug) every 3 months for 1 year. Bone mineral density was measured at the beginning of the study and was repeated at 6 months and 1 year. Women who received zoledronic acid did not experience any bone loss whereas women assigned to placebo experienced an average 4% bone loss at the lumbar spine and 2% bone loss at the hip. Studies using oral bisphosphonates such as Risedronate are also currently on-going. Another medication called Denosumab, which is not yet FDA approved, may be available in the future to treat and prevent cancer therapy-induced bone loss.

Vitamin D and Bone Health
Vitamin D is very important for bone health as it is fundamental for the intestinal absorption of calcium. When our vitamin D stores are low we cannot adequately absorb calcium. To maintain normal blood levels of calcium when vitamin D is low, the body obtains it from our biggest source, the skeleton. In order to mobilize calcium from the bones, osteoclasts degrade bone and release calcium and phosphorus in the blood stream. Chronically low levels of Vitamin D lead to continual degradation of bone, an additional risk factor for bone loss. Moreover, when our vitamin D levels are low the new bone matrix deposited by the osteoblasts cannot be adequately mineralized. Low mineralization of the bone matrix can lead to osteomalacia. Osteomalacia is usually a very painful condition characterized by diffuse bone/joint pains, muscle weakness particularly when climbing steps and profound fatigue.

A recent study showed 74% of premenopausal women diagnosed with breast cancer were found to be vitamin D deficient. Supplementation for these women for an entire year with 400 units of vitamin D and 1000 mg calcium was not sufficient to improve their vitamin D levels. It is important to note African-American women are at higher risk of vitamin D deficiency as the pigment melanin in the skin is a very effective sun screen.

A vitamin D level between 40-50 ng/ml is advisable and these levels can be checked by your physician.

Food Calcium (mg)
Swiss cheese, 1 1/2 oz.  408
Fruit yogurt (low fat), 8 oz. 345
Skim milk (fat free), 1 cup 306
Mozzarella cheese stick (part skim), 1 oz. 183
Sardines (Atlantic, in oil, drained), 3 oz. 325
Tofu (firm), 1/2 cup 253
Canned pink salmon with bones, 3 oz. 181
Frozen cooked collard greens, 1/2 cup 179
Spinach (cooked from frozen), 1/2 cup 146
Orange, medium size 52
Where Do We Find Vitamin D?
Our body has the capability of producing vitamin D when our skin is exposed to the sun.

Sun screens are a very effective method of blocking vitamin D production by the skin.

Of course we are not advocating stopping sun screen use, but reminding the reader of the importance of keeping adequate vitamin D stores.

The major source of dietary vitamin D is found in fatty fish such as salmon, mackarel and sardines, but in order to maintain adequate levels of vitamin D these types of fish would have to be consumed on a daily basis! Consuming this amount of fish is not a feasible way of obtaining vitamin D, especially considering our Midwestern diet. Vitamin D enriched milk cannot be considered a reliable source of this vitamin either as the less fat in milk the less vitamin D. There is a bit of vitamin D in egg yolk and mushrooms, but otherwise limited quantities are found in food.

Given the limited amount of vitamin D in oods and the need to continue to use sunscreen, supplementation becomes the most reliable way of maintaining normal levels of vitamin D.

What Can We Do to Maintain Strong and Healthy Bones
When a woman is diagnosed with breast cancer, a baseline bone mineral density should be obtained along with a 25-OH vitamin D level prior to starting chemotherapy. If low mineral bone density is identified a work-up for secondary causes of bone loss may be needed. If Vitamin D levels are low at time of diagnosis then supplementation will be recommended. If the level is in the deficient-insufficient range (vitamin D below 30 ng/ml) I usually recommend prescription strength vitamin D supplementation in the form of Ergocalciferol (vitamin D2), 50,000 units once a week for approximately 12 consecutive weeks followed by daily over the counter vitamin D, 1000 units daily. All women with breast cancer should also have a total calcium intake of 1200-1500 mg daily either by dietary intake or by supplementation.

Smoking and excessive alcohol use (more than six drinks per week) negatively impact bone mass and appropriate modifications should be implemented. Excessive caffeine intake also has been implicated in reducing calcium absorption. Exercise is necessary for a healthy skeletal system and walking is an excellent weight bearing exercise. Population studies have shown physically active individuals are 20-50% less likely to have a hip fracture as compared to their sedentary counterparts. Any type of exercise is important to maintain muscle strength, improve balance, and prevent falls, and women are encouraged to exercise 30-60 minutes at least four-five times per week.

Addressing bone loss in young women diagnosed with breast cancer is an important aspect of a woman’s total cancer care and there are many positive steps young survivors can take to keep their bones healthy.

References
Rozenberg S, et al. Risks of osteoporosis associated with breast cancer treatment: the need to access preventive treatment. Maturitas 2009;64:1-3.

Rossouw JE, 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 American Medical Association, 2002;288:321-33.

Hadji P, et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Annals of Oncology 2008;19:1407-1416.

Hershman DL, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. Journal of Clinical Oncology, 2008;26:4739-4745.

Crew KD, et al. High prevalence of Vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy. J Clin Oncology 2009;27:2151-2156.