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Focus on Bone Health, Breast Cancer Prevention and Treatment With Bisphosphonate Therapy

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By Marjorie Green, Associate Professor, Department of Breast Medical Oncology

Over 190,000 women will be diagnosed with breast cancer in the United States during 2009. Research efforts are designed to not only improve the treatment of breast cancer but also to help evaluate methods that can prevent breast cancer development. At the 32nd annual CTRC-AACR San Antonio Breast Cancer Symposium, researchers will be presenting data from multiple studies examining the use of a commonly prescribed class of medicines -- bisphosphonates.

Bisphosphonates are medications that interfere with the normal remodeling (breakdown and then rebuilding) of bone that occurs in all people. Our bones are constantly being taken apart by cells called osteoclasts and then rebuilt by cells called osteoblasts. Bisphosphonates stop osteoclasts from destroying bone so there is less bone loss and bone can be rebuilt. 

Bisphosphonates are commonly used to treat bone loss in women -- both osteopenia (early bone loss) as well as osteoporosis (severe bone loss). Unfortunately, many women who receive therapy for breast cancer either already have bone loss at the time of their cancer diagnosis or their medical therapies used to treat breast cancer put them at risk for accelerated bone loss.

Z-FAST trial

At the meeting, Adam Brufsky, M.D., presented data regarding the Z-FAST trial where patients received an antiestrogen therapy for breast cancer, letrozole. Letrozole is an anti-estrogen medication that lowers the body's production of estrogen and is commonly used to treat breast cancer. Lowering estrogen levels can, unfortunately, accelerate bone loss. The Z-FAST study was designed to see if starting the bisphosphonate zoledronic acid at the time of initiation of letrozole could help prevent bone loss.

Patients on this study were randomized to start both letrozole and zoledronic acid together (the "upfront group") or to start letrozole and have their bone health followed (the "delayed group"). If patients in the delayed group who were not started on zoledronic acid developed severe worsening of bone loss or developed a fracture in the bone, then zoledronic acid was started. 

Patients in the upfront group of combined letrozole and zoledronic acid were found to have marked increase in bone strength at the end of five years of therapy when compared to women who were started on the letrozole only. Patients in the delayed group started on letrozole alone actually lost bone strength.

The patients who started the zoledronic acid later did rebuild their bone when zoledronic acid was finally started. The study describes a slightly higher number of fractures in the group who delayed initiation of zoledronic acid (12.4%) versus those who started immediately (10.7%). However, it isn't certain that starting zoledronic acid at the beginning of anti-estrogen therapy is necessary for all patients. Other studies (example: the ATAC study) have shown that women with normal bone strength at the beginning of anti-estrogen therapy don't develop osteoporosis from their breast cancer treatment, even though there is some bone loss seen.

Other studies

Recently, there has been evidence that bisphosphonates may have another role in addition to helping strengthen the bone, and that is possibly to interfere with the growth and development of breast cancer. An Austrian study evaluating the use of the bisphosphonate zoledronic acid as treatment of young women with breast cancer found that zoledronic acid not only prevented bone loss, but it also lowered the risk of breast cancer recurrence and development of new breast cancers.

At the  meeting, two studies will be presented that suggest that bisphosphonates used to treat bone loss may also help to prevent breast cancer development. The Women's Health Initiative study describes that use of bisphosphonates lowers the risk of developing breast cancer by more than 30%, and a similar reduction in the risk of developing breast cancer will be described by a group from Israel (Rennert et al). These studies were not specifically designed to determine if using a bisphosphonate will prevent the development of breast cancer. The results are observations comparing women who took bisphosphonates primarily for bone health reasons, compared with women who did not take bisphosphonates. Regardless, the findings are very exciting and will likely lead to additional research to determine if these medications can be used to prevent development of breast cancer in women.

Denosumab

Finally, newer medications have been developed that may help preserve bone strength and prevent complications from having breast cancer that has spread to the bone better than the bisphosphonates. Denosumab is an antibody that prevents osteoclasts from developing and thus prevents the destruction of bone. More than 2,000 patients with breast cancer that had spread to the bone were treated with either denosumab or the bisphosphonate zoledronic acid. Denosumab appears to lower the risk of fractures in the bone from cancer more effectively than zoledronic acid. Ongoing studies will help to clarify the role of this medication.

1 Comment

I am interested to know if the study populations were evaluated for levels of serum estradiol. It would make perfect sense (at least to me) that women who have poor bone health and prescribed a bisphosphonate are also probably estrogen deprived. The question then becomes is the reduction in reported breast cancer a direct effect from the bisphosphonate therapy or from the inherently low level of serum estradiol?

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